Methods of treating ophthalmic conditions with enhanced penetration compositions of bimatoprost and timolol

ABSTRACT

The present invention provides methods of treating one or more ocular conditions, such as, e.g., elevated intraocular pressure, glaucoma (e.g., open-angle glaucoma), or both comprising administration of effective amounts of pharmaceutically acceptable and ophthalmologically suitable compositions. The invention further provides compositions for use in such methods comprising a therapeutically effective amount of a bimatoprost compound, a therapeutically effective amount of a timolol compound, benzalkonium chloride, a viscosity enhancer component, and a penetration enhancer component other than benzalkonium chloride. Further, in aspects the invention also provides processes for the preparation of compositions for use in such methods.

RELATED APPLICATIONS/PRIORITY

This patent Application claims priority to presently pending U.S.Provisional Patent Application No. 63/322,211 filed Mar. 21, 2022,entitled “ENHANCED PENETRATION OPHTHALMIC COMPOSITIONS OF BIMATOPROSTAND TIMOLOL;” presently pending U.S. Provisional Patent Application No.63/322,223 filed Mar. 22, 2022, entitled “METHOD OF TREATING OPHTHALMICCONDITIONS WITH ENHANCED PENETRATION COMPOSITIONS OF BIMATOPROST ANDTIMOLOL;” and presently pending U.S. Provisional Patent Application No.63/322,226 filed Mar. 22, 2022, entitled “OPHTHALMIC GEL COMPOSITIONS OFBIMATOPROST AND TIMOLOL AND ASSOCIATED METHODS.” This application claimsthe benefit of priority to, and incorporates by reference the entiretyof, these above-referenced priority applications.

FIELD OF THE INVENTION

The invention primarily relates to ophthalmic compositions comprising abimatoprost compound and a timolol compound for use in treating elevatedintraocular pressure, and related methods of their manufacture and use.

BACKGROUND OF THE INVENTION

Glaucoma is a widespread, sight-threatening disease usually associatedwith an elevated intraocular pressure (IOP) which, if left untreated ortreated unsuccessfully, can cause irreversible optic nerve and visualfield damage. Management of glaucoma requires life-long treatment,typically by application of eye drops.

A large range of eye drops, containing beta-blockers, alpha-2 agonists,carbonic anhydrase inhibitors, and prostaglandins, are available fortreating glaucoma. For over 20 years, prostaglandin analogues (oftenfrequently referred to simply as “prostaglandins”) have beensuccessfully used as a first-line treatment in glaucoma patients.Developed and marketed prostaglandins used in treatment of eyeconditions include latanoprost (initially developed and sold under thebrand name XALATAN™), travoprost (sold as, e.g., TRAVATAN Z™) tafluprost(sold as, e.g., ZIOPTAN™), and bimatoprost (developed and sold under thebrand name LUMIGAN®).

Despite overlapping and/or similar functionality and properties,prostaglandins have been repeatedly demonstrated to exhibit significantdifferences in both biological/cellular-level effects and physiologicallevel effects, such as, e.g., with respect to irritation and otheradverse effects. For example, pharmacologic and pharmacokinetic datasuggest the existence of a unique bimatoprost receptor, distinct fromthe known FP receptors; however, this receptor is yet to be cloned, andbimatoprost has not been shown to work independent of FP receptoractivation. See, e.g., Winkler N S et al. J Ocul Pharmacol Ther. 2014;30(2-3):102-109. doi:10.1089/jop.2013.0179. Another study reports thatbimatoprost appears to reduce the IOP of patients who are unresponsiveto latanoprost, suggesting that the prostamide bimatoprost and the FPreceptor agonist latanoprost stimulate different receptor populations.See, e.g., Gandolfi S A, Cimino L. Ophthalmology. 2003 March;110(3):609-14. Cytokine expression studies relating to prostaglandinshave also evidenced that these compounds stimulate different cytokinepathways. For example, MMP-9 expression was found to be higher in eyesreceiving latanoprost, while the MMP-2 expression was higher in eyesreceiving bimatoprost, with MMP1 protein levels being higher in theformer. See, e.g., Reddy S et al. PLoS One. 2018 Aug. 6; 13(8):e0201740.doi: 10.1371/journal.pone.0201740. PMID: 30080906; PMCID: PMC6078293.Differences in fibronectin expression and in aquaporin-1 expression inresponse to bimatoprost as compared to latanoprost also has been linkedto variability in the IOP-lowering efficacy of the compounds in somestudies. See, e.g., Li X et al. PLoS One. 2016 Mar. 24; 11(3):e0151644.doi: 10.1371/journal.pone.0151644. PMID: 27011234; PMCID: PMC4807090. Interms of distribution, bimatoprost has been shown to reach targettissues differently than latanoprost, wherein intact bimatoprost hasbeen identified in the target ciliary body indicating its directinvolvement in the reduction of IOP, and further wherein bimatoprost hasbeen linked with poor corneal penetration in comparison to latanoprostand travoprost. See, e.g., Eisenberg, D. Ophthalmology. 110(9):1861-1862 (2003). Topical bimatoprost therapy has been demonstrated tocause more periocular changes than latanoprost therapy. See, e.g.,Karslioğlu M Z et al. Turk J Med Sci. 2015; 45(4):925-30. PMID:26422869. Prostaglandin products are associated with differences inactive pharmaceutical ingredient (API) stability, as well, withbimatoprost shown to remain stable under certain conditions, withlatanoprost and travoprost experiencing degradation under suchconditions. See, e.g., Johnson T V et al. J Ocul Pharmacol Ther. 2011Feb.; 27(1):51-9. doi: 10.1089/jop.2010.0115. Epub 2010 Nov. 30. PMID:21117945; PMCID: PMC3038126.

The prostaglandins have also been demonstrated to exhibit clinicaldifferences. For example, see, e.g., Parrish R K et al. Am J Ophthalmol.2003 May; 135(5):688-703. doi: 10.1016/s0002-9394(03)00098-9. PMID:12719078, wherein fewer latanoprost-treated patients reported ocularadverse events (P<0.001, latanoprost vs bimatoprost), fewer reportedhyperemia (P=0.001, latanoprost vs bimatoprost), and average hyperemiascores were lower at week 12 (P=0.001, latanoprost vs bimatoprost), and,while latanoprost, bimatoprost, and travoprost have in some (other)studies been shown to be comparable in their ability to reduce IOP inOAG and OH patients, latanoprost exhibited greater ocular tolerability.That said, nausea, vomiting and sometimes diarrhea should be consideredas adverse effects of travoprost and latanoprost. For example, accordingto the case report cited in Yu M et al. BMJ Case Rep. 2009; doi:10.1136/bcr.08.2008.0618. Epub 2009 Feb. 26. PMID: 21686721; PMCID:PMC3028105, bimatoprost did not induce the same gastrointestinal adverseeffects as travoprost and latanoprost, probably due to its differentchemical structure and receptors. Still further, Gandolfi S et al. AdvTher. 2001 May-June; 18(3):110-21. doi: 10.1007/BF02850299. PMID:11571823 reports that conjunctival hyperemia was more commonlyassociated with bimatoprost therapy, while headache was more frequentwith latanoprost in a three-month comparison of bimatoprost andlatanoprost in patients with glaucoma and ocular hypertension. However,bimatoprost provided lower mean pressures than latanoprost at every timepoint studied and was statistically superior in achieving low targetpressures. Id. Patients using travoprost or bimatoprost have been shownto have a significantly lower rate of adjunctive medication use comparedto patients starting on latanoprost monotherapy (22.5%, 23.2%, and30.2%, respectively), reflecting differences in overall efficacy ofprostaglandins. See Covert D et al. Curr Med Res Opin. 2006 May;22(5):971-6. doi: 10.1185/030079906x104777. PMID: 16709319.

Bimatoprost is specifically classified as prostamide and a syntheticanalogue of prostaglandin F2a (PGF2a) with potent ocular hypotensiveactivity.

Bimatoprost lowers IOP in patients with glaucoma or ocular hypertensionby increasing outflow of aqueous humor through both the trabecularmeshwork and uveoscleral routes.

The art is replete with both postulated and on-market (e.g., LUMIGAN®)bimatoprost ophthalmic bimatoprost compositions. Exemplary bimatoprostcompositions disclosed in the patent art are described in, e.g., UnitedStates (US) Patent Numbers (Nos.) U.S. Pat. Nos. 6,646,001, 7,851,504,8,309,605, 8,338,479, 8,343,949, 8,586,630, 8,691,802, 8,933,120, and9,241,918; United States Patent Publication Number 2013/0245124; and,e.g., PCT Publication Numbers WO2009013434, WO2010102078, WO2016198434,WO2018185788, and WO2020178672. However, while a popular intraocularpressure reducing agent, bimatoprost is known in the art as causingincreased side effects over other prostaglandin compounds.

For example, Inoue provides a compilation of the myriad of side effectspatients must navigate when managing glaucoma treatment in thepublication “Managing adverse effects of glaucoma medications,” ClinOphthalmol, 2014; 8:903-913. Therein, many publications are cited asdisclosing the challenges presented by bimatoprost use. Honrubia, et.al., in “Conjunctival Hyperaemia with the Use of Latanoprost VersusOther Prostaglandin Analogues in Patients with Ocular Hypertension orGlaucoma: Meta-Analysis of Randomized Clinical Trials,” (in Br JOphthalmol. 2009; 93(3):316-321) discloses that conjunctival hyperemiaoccurred significantly less often with latanoprost than with travoprostor bimatoprost. Aptel, et. al., in “Efficacy and tolerability ofprostaglandin analogs. A meta-analysis of randomized controlled clinicaltrials,” (in J Glaucoma. 2008; 17(8):667-673) discloses that systematicreviews have shown conjunctival hyperemia to be more likely to occurwith travoprost or bimatoprost use than latanoprost use. Crichton, et.al., in “Ocular surface tolerability of prostaglandin analogues andprostamides in patients with glaucoma or ocular hypertension,” (in AdvTher. 2013; 20(3):260-270) and Inoue, et. al., in “Adverse periocularreactions to five types of prostaglandin analogs,” (in Eye. 2012;26(11):1465-1472) disclose the reported incidence of conjunctivalhyperemia differing between various prostaglandin analogs and occurringmore often with bimatoprost use than with other prostaglandin analogs,and further report that the incidence of eyelash lengthening/bristlingwas demonstrated to be higher in bimatoprost than with otherprostaglandins (travoprost, latanoprost, and tafluprost).

Eyelash growth-specific findings are further validated by Wester, et.al. (in Ophthalmology. 2010; 117(5):102-1031) wherein a gel formulationof bimatoprost is utilized specifically to promote eyelash growth.Similarly, Giannico, et. al., in “Eyelash Growth Induced by TopicalProstaglandin Analogues, Bimatoprost, Tafluprost, Travoprost, andLatanoprost in Rabbits,” (in J Ocular Pharmacol Ther. 2013;29(9):817-820) and Priluck J C et. al., (section editor Green) in“Latisse-Induced Periocular Skin Hyperpigmentation,” (in Ophthalmol.2010; 128(6):792-793) report that in a study of four types ofprostaglandin analogs administered to rabbits, those receivingbimatoprost experienced significant eyelash growth. Still furthercomplicating the use of bimatoprost, Priluck further discloses thateyelid skin hyperpigmentation can be a problem; an effect demonstratedby many other if not all prostaglandins, and further demonstrating thenuanced nature of ophthalmic bimatoprost product development and thecare which may be taken to avoid unwanted side effects. While in certaincircumstances, eyelash growth, or even, hypothetically, skinpigmentation may be desirable where such a targeted outcome isbeneficial, such effect is likely very unwelcome in the targetindication of glaucoma.

Even further, bimatoprost, when used in the treatment of glaucoma, hasbeen reported as inducing iris pigment changes (inducing an increasedpigment change over that of tafluprost); see, e.g., Inoue et. al., in“Adverse reaction after use of latanoprost in Japanese glaucomapatients,” Nihon Ganka Gakkai Zasshi., 2006; 110(8):581-587. Deepeningof the upper eye lid sulcus from topical application of bimatoprostduring glaucoma treatment is yet an additional side effect resultingfrom bimatoprost treatment of glaucoma, often occurring more frequentlyin bimatoprost recipients than in those using alternative prostaglandins(see, e.g., Peplinski, et. al., in “Deepening of lid sulcus from topicalbimatoprost therapy,” (in Optom Vis Sci. 2004; 81(8):574-577); Park, et.al., in “Changes to upper eyelid orbital fat from use of topicalbimatoprost, travoprost, and latanoprost,” (in Jpn J Ophthalmol. 2011;55(1):22-27); Inoue, et. al., in “Deepening of the upper eyelid sulcuscaused by 5 types of prostaglandin analogs,” (in J Glaucoma. 2013;22(8):626-631); and Shah, et. al., in “A cross-sectional survey of theassociation between bilateral topical prostaglandin analogue use andocular adnexal features,” (in PLoS One. 2013; 8(5):e61638).

The above effects are common in addition to the physical discomfortknown to be common with bimatoprost use, including red and itchyeyelids, general ocular irritation and eye pain. Taken together, sucheffects could, still, arguably be endured if the alternative is the lossof eyesight due to uncontrolled intraocular pressure. While popular intheir use, in a sub-population of patients with glaucoma or ocularhypertension, prostaglandins by themselves often do not producesufficient pressure reduction to reach the desired target. As a result,many such patients require treatment with more than one medication,e.g., more than a single prostaglandin.

In an effort to increase efficacy, other classes of actives have beenproposed in combination with prostaglandins such as bimatoprost.β-adrenoreceptor antagonists or β-blockers are often used as add-ontherapy for patients who are already on a prostaglandin therapy. Incertain cases where surgery is not indicated, β-blockers havetraditionally been the drugs of choice for treating glaucoma. Topicalβ-blockers reduce the IOP by blockade of sympathetic nerve endings inthe ciliary epithelium causing a fall in aqueous humor production. Thecompound timolol is one such β-blocker.

Timolol is a beta-adrenergic agent, chemically know as(-)-1-(tert-butylamino)˜3-[(4-morpholino-1,2,5-thiadiazol-3-yl)-oxy]˜2-propanoland having the following molecular structure:

Timolol is available in the United States as single drug or as a fixeddose combination with drugs like dorzolamide or brimonidine for itsophthalmic use.

While having demonstrated IOP-reducing activity, like prostaglandins andespecially bimatoprost, the use of timolol has come under scrutiny.Known side effects of timolol, e.g., timolol maleate, include temporaryblurred vision, burning, stinging, itching, redness, watering, dryness,general irritation, and even headache. Inoue, et. al. in Ocular factorsrelevant to anti-glaucomatous eyedrop-related keratoepitheliopathy,” (inJ Glaucoma. 2003; 12(6):480-485) further describe that ocular adversereactions to beta-blockers include conjunctival allergies, conjunctivalinjection, corneal epithelium disorders, blepharitis, and ocularpemphigoid, and goes one to describe a reduction in corneal sensitivityby such agents, leading to a reduction in reflective tearing andresulting in corneal epithelium disorders. Timolol is known to causethis effect and as reported by Inoue, was associated with a greaternumber of cases of corneal epithelium disorders than the use ofcarteolol.

Despite all such concerns related to each active individually, themarket remains desperate for an efficacious treatment of glaucoma or ata minimum a sufficiently efficacious treatment short of surgicalintervention, and, accordingly, the combination of timolol andbimatoprost specifically has been described in the patent literature.

U.S. patent. Nos. U.S. Pat. Nos. 8,906,907, 8,629,140, 8,618,093,9,474,760, and 10,045,997 describe compositions for, and related methodsof, treating ocular hypertension including composition(s) comprisingabout 0.5% w/v timolol or pharmaceutically acceptable salts thereof andabout 0.03% w/v bimatoprost.

U.S. Patent Publication No. 2019/0076442 describes preservative freeophthalmic pharmaceutical composition(s) for topical administrationcomprising bimatoprost or ophthalmological acceptable salts thereof andtimolol or ophthalmological acceptable salts thereof for use in treatingocular hypertension and glaucoma.

U.S. patent. Nos. U.S. Pat. Nos. 9,579,328 and 9,248,135 describescomposition comprising a prostaglandin agent and a vasoconstrictoragent, wherein said vasoconstrictor agent is present in asub-therapeutic amount. The said prostaglandin agent can be bimatoprostand the vasoconstrictor agent can be timolol and the sub-therapeuticamount is an amount less than about 0.25% w/w or less.

U.S. patent. Nos. U.S. Pat. Nos. 9,061,034; 10,058,560, 9,763,958 and9,078,854 also describe preservative free bimatoprost and timololcomposition(s) for lowering intraocular pressure in a patient, whereincomposition(s) comprises about 0.03% w/v bimatoprost and about 0.5% w/vtimolol. Therein, it is disclosed that such composition(s) have anincreased intraocular pressure lowering ability compared to the samecomposition preserved with benzalkonium chloride (BKC), a componentwhich is discussed further elsewhere in this section.

U.S. Patent Publication No. US 2014/0088107 describes an aqueousophthalmic preparation comprising a PGF2a analogue and at least onepolyvinyl alcohol and the use thereof for the treatment of glaucoma andocular hypertension. The PGF2a analogue disclosed in this art includesbimatoprost and the composition may further contain 0-adrenergicreceptor antagonists which includes timolol. Like the precedingreferences, a key aim of the invention disclosed in US 2014/0088107 isthe provision of composition(s) which are essentially preservative-free.A specific example provided therein includes a combination of andtimolol (see Table 2) wherein the bimatoprost is present in an amountrepresenting about 0.03% of the composition and the composition is freeof preservatives.

While there are no approved products available in the United Statesproviding the combination of bimatoprost and timolol or pharmaceuticallyacceptable salts thereof at the time of this filing, the combination ofbimatoprost 0.03% and timolol 0.5% is available outside of the UnitedStates, e.g., in countries such as Europe and India (see, e.g.,GANFORT®), as composition(s) either with or without preservatives suchas benzalkonium chloride. The combination of bimatoprost 0.01% andtimolol maleate in an amount equivalent to 5 mg/mL (0.5% w/v) with 0.1mg/mL (0.01% w/v) benzalkonium chloride as a preservative agent isavailable in India (Bimat LS TM Eye Drops by Ajanta Pharma).

Such-fixed dose combination therapies for the treatment of glaucomathemselves are often questioned, as has been reported by Aptel, et. al.in, “Efficacy and tolerability of prostaglandin-timolol fixedcombinations: a meta-analysis of randomized clinical trials,” (in Eur JOphthalmol. 2012; 22(1):5-18). Therein Aptel describes that adversereactions to the two main agents included in fixed-combination eye dropsinclude those experienced when each agent is administered alone.However, because fixed-combination medications are often administered atlower frequencies, eye surface disorders caused by preservatives canoccur in lower incidences, though certain combinations outperformothers. A meta-analysis of the association between fixed-combination eyedrop use and hyperemia conjunctiva showed that patients usingbimatoprost plus timolol were 1.16 to 2.00 times more likely to developthe condition than patients using latanoprost plus timololfixed-combination eye drops, and patients using travoprost plus timololfixed-combination eye drops were 5.99 times more likely to develop thecondition than patients using latanoprost plus timolol fixed-combinationeye drops. Accordingly, the development of fixed-dose drug combinationshas proven nuanced and unpredictable.

The incorporation of benzalkonium chloride as a preservative componentof ophthalmic compositions provides its own challenges to productdevelopment. In 2001, the FDA approved LUMIGAN®, a sterile ophthalmicsolution containing 0.03% bimatoprost (“LUMIGAN® 0.03%”) developed byALLERGAN, a leading, global ophthalmologic pharmaceutical company. Whilelacking a β-blocker, the LUMIGAN® 0.03% composition comprisesbenzalkonium chloride (“BKC”) 0.05 mg/mL (0.005% or 50 ppm).LUMIGAN®0.03% is indicated for the reduction of elevated intraocularpressure in patients with open-angle glaucoma (OAG) or ocularhypertension (OH). LUMIGAN® 0.03% became a successful product, with 2011sales of more than $600 million US dollars. However, LUMIGAN® 0.03% wasknown to also cause hyperemia (eye redness) that led many patients todiscontinue use of the product. Vasodilatation in the conjunctiva, themost frequent adverse effect, led to about 3% of patients discontinuingtherapy. See, e.g., Sherwood M, et al. Surv Ophthalmol. 2001;45:S361-S368 and Hollò G. Exper Opin Drug Saf. 2007; 6:45-52. Anincreasing body of research also pointed to benzalkonium chloride (BKC)causing ophthalmological side effects. In fact, BKC was reported toconsistently demonstrate toxic effects in laboratory, experimental, andclinical studies, causing tear film instability, loss of goblet cells,conjunctival squamous metaplasia and apoptosis, disruption of thecorneal epithelium barrier, and damage to deeper ocular tissues.Baudouin C et al. Prog Retin Eye Res. 2010 Jul; 29(4):312-34. doi:10.1016/j.preteyeres.2010.03.001. PMID: 20302969. Such issues led to theconclusion that, “Care should therefore be taken to avoid the long-termuse of preservatives, otherwise a less toxic alternative to benzalkoniumchloride should be developed, as this weakly allergenic but highly toxiccompound exerts dose- and time-dependent effects,” (Baudoin, et. al.,“Preservatives in eyedrops: the good, the bad and the ugly,” Prog RetinEye Res. 2010 Jul; 29(4):312-34). The authors further reported, “On thebasis of all these experimental and clinical reports, it would beadvisable to use benzalkonium-free solutions whenever possible . . . ”Id. Patients can experience hypersensitivity reactions with BKC and BKCmay be absorbed by soft contact lenses creating challenges for contactlens users. PCT Publication Number WO2018185788 is an example of thepatent art advocating for the same BKC-free formulation approach.Attempts to replace benzalkonium chloride with other actives has provenchallenging. For example, see the disclosure of US Patent PublicationNo. 2014/0088107 cited previously (“′107”), which discloses, “Due to thedrawbacks of the use of benzalkonium chlorides, numerous attempts havebeen made to develop ophthalmic preparations comprising PGF2a analogueswithout the use of benzalkonium chlorides. One such product is soldunder the trade name “TRAVATAN Z”, wherein benzalkonium chloride isreplaced by a complex system comprising polyoxyl 40 hydrogenated castoroil, boric acid, propylene glycol, sorbitol, and zinc chloride. Afurther preparation that is marketed as being preservative-free is soldin parts of Europe under the trade name “TAFLOTAN sine” and comprisesdisodium EDTA, glycerol and Polysorbate 80 in place of benzalkoniumchloride. Despite the fact that both preservative-free” preparations dono longer contain benzalkonium chlorides, they now contain several othercompounds instead, and, in particular, in both cases surfactants. Thepresence of multiple compounds obviously increases the chances ofsensitization of a patient to one or several of the ingredients, as wellas making the production thereof more expensive. Furthermore, thepresence of surfactants might still lead to problems during long-termuse.” (See Paragraphs [0007]-[0008]). The ′107 art proposes use ofpolyvinyl alcohol as a solution to the provision of a preservative freecomposition (solution) of a single PGF2a analogue. In another similarexample provided by the prior cited art, U.S. Pat. No. 7,851,504discloses incorporation of 100-200 ppm benzalkonium chloride whichincreased permeability of bimatoprost into ocular tissue (beyondpreservation effect), while adding TPGS decreased permeability comparedto 100-200 ppm BKC. Thus, while the art seeks to replace BKC, solutionssometimes still remain elusive.

The art provided above has been collected over the course of at least 20years. Yet glaucoma sufferers continue to search for efficacious optionsto combat the debilitating disease, demonstrating that the developmentof new compositions and treatment regimens for the effective treatmentof glaucoma require the application of inventive ingenuity.

Construction, Terms, and Acronyms

This section offers guidelines for reading this disclosure. The intendedaudience for this disclosure (“readers”) are persons having ordinaryskill in the practice of technologies discussed or used herein. Readersmay also be called “skilled persons,” and such technologies called “theart.” Terms such as “understood,” “known,” and “ordinary meaning,” referto the general knowledge of skilled persons.

The term “uncontradicted” means not contradicted by this disclosure,logic, or plausibility based on knowledge of skilled persons.

Disclosed here are several different but related exemplary aspects ofthe invention (referred also to as, e.g., “cases,” “facets,” or“embodiments”). The invention encompasses all aspects, as describedindividually and as can be arrived at by any combination of suchindividual aspects. The breadth and scope of the invention should not belimited by any exemplary embodiment(s). No language in this disclosureshould be construed as indicating any element/step is essential to thepractice of the invention unless such a requirement is explicitlystated. Uncontradicted, any aspect(s) can be combined with any otheraspect(s).

Uncontradicted, all technical/scientific terms used here generally havethe same meanings as commonly understood by skilled persons, regardlessof any narrower examples or descriptions provided here (including anyterm introduced initially in quotations). However, aspects characterizedby the inclusion of elements, steps, etc., associated with specificdescriptions provided here are distinct embodiments of the invention.Uncontradicted, disclosure of any aspect using known terms, which termsare narrowed by example or otherwise in this disclosure, implicitlydiscloses related aspects in which such terms are alternativelyinterpreted using the broadest reasonable interpretation of skilledpersons.

Uncontradicted, “or” means “and/or” here, regardless of any occasionalinclusion of “and/or” (e.g., phrases such as “A, B, or C” and “A, B,and/or C” simultaneously disclose aspects including (1) all of A, B, andC; (2) A and C; (3) A and B; (4) B and C; (5) only A; (6) only B; and(7) only C (and also support sub-groupings, such as “A or B,” “A or C,”etc.)).

Uncontradicted, “also” means “also or alternatively.” Uncontradicted,“here” & “herein” mean “in this disclosure.” The term “i.a.” means“inter alia” or “among other things.” “Also known as” is abbreviated“aka” or “AKA.” “Elsewhere” means “elsewhere herein.”

For conciseness, symbols are used where appropriate. E.g., “&” is usedfor “and,” & “˜” for “about.” Symbols such as <and> are given theirordinary meaning (e.g., “≤” means “less than or equal to” & “≥” means“greater than or equal to”). A slash “/” can represent “or” (“A/B” means“A or B”) or identify synonyms of an element, as will be clear fromcontext.

The inclusion of “(s)” after an element or a step indicates that ≥1 ofsuch an element is present, step performed, and the like. E.g.,“element(s)” means both 1 element or ≥2 elements, with the understandingthat each thereof is an independent aspect of the invention.

Use of the abbreviation “etc.” (or “et cetera”) in association with alist of elements/steps means any or all suitable combinations of therecited elements/steps or any known equivalents of such recitedelements/steps for achieving the function(s) of such elements/steps thatare known in the art. Terms such as “and combinations,” or “orcombinations” regarding listed elements/steps means any or allpossible/suitable combinations of such elements/steps.

Aspects may be described as suitable for use(s) disclosed herein.Uncontradicted, terms such as “suitability” means acceptable orappropriate for performing a particular function/achieving particularstate(s)/outcome(s), and typically means effective, practical, andnon-deleterious/harmful in the context the term is used. E.g.,uncontradicted, the term “suitable” means appropriate, acceptable, or incontexts sufficient, or providing at least generally or substantiallyall of an intended function, without causing or imparting significantnegative/detrimental impact.

Uncontradicted, heading(s) (e.g., “Construction, Terms . . . ”) andsubheadings are included for convenience and do not limit the scope ofany aspect(s). Uncontradicted, aspect(s), step(s), or element(s)described under one heading can apply to other aspect(s) orstep(s)/element(s) here.

Ranges of values are used to represent each value falling within suchrange that are within an order of magnitude of the smallest endpoint ofthe range without having to explicitly write each value of the range.E.g., a recited range of 1-2 implicitly discloses each of 1.0, 1.1, 1.2,. . . 1.9, and 2.0 and 10-100 implicitly discloses each of 10, 11, 12, .. . 98, 99, and 100). Uncontradicted, all ranges include the range'sendpoints, regardless of how a range is described. E.g., “between 1-5”includes 1 and 5 in addition to 2, 3, and 4 (and all numbers betweensuch numbers within an order of magnitude of such endpoints, e.g., 1.0,1.1, . . . 4.9, and 5.0). For the avoidance of doubt, any number withina range, regardless of the order of magnitude of the number, is coveredby the range (e.g., a range of 2-20 covers 18.593).

Terms of approximation (e.g., “about,” “˜,” or “approximately”) are used(1) to refer to a set of related values or (2) where a precise value isdifficult to define (e.g., due to limits of measurement).Uncontradicted, all exact values provided here simultaneously/implicitlydisclose corresponding approximate values and vice versa (e.g.,disclosure of “about 10” provides explicit support for the use of 10exactly in such aspect/description). Ranges described with approximatevalue(s) include all values encompassed by each approximate endpoint,regardless of presentation (e.g., “about 10-20” has the same meaning as“about 10-about 20”). The scope of value(s) encompassed by anapproximate term typically depends on the context of the disclosure,criticality or operability, statistical significance, understanding inthe art, etc. In the absence of guidance here or in the art for anelement, terms such as “about” when used in connection with an elementshould be interpreted as ±10% of the indicated value(s) and implicitlydisclosing ±5%, ±2%, ±1%, and ±0.5%.

Lists of aspects, elements, steps, and features are sometimes employedfor conciseness. Unless indicated, each member of each list should beviewed as an independent aspect. Each aspect defined by any individualmember of a list can have, and often will have, nonobvious propertiesvis-a-vis aspects characterized by other members of the list.

Uncontradicted, the terms “a” and “an” and “the” and similar referentsencompass both the singular and the plural form of the referencedelement, step, or aspect. Uncontradicted, terms in the singularimplicitly convey the plural and vice versa herein (in other words,disclosure of an element/step implicitly discloses corresponding use ofsuch/similar elements/steps and vice versa). Hence, e.g., a passageregarding an aspect including X step supports a corresponding aspectincluding several X steps. Uncontradicted, any mixed use of a referentsuch as “a” in respect of one element/step or characteristic and “one ormore of” with respect to another element/step or characteristic in aparagraph, sentence, aspect, or claim, does not change the meaning ofsuch referents. Thus, for example, if a paragraph describes acomposition comprising “an X” and “one or more Ys,” the paragraph shouldbe understood as providing disclosure of “one or more Xs” and “one ormore Ys.”

“Significant” and “significantly” mean results/characteristics that arestatistically significant using ≥1 appropriate test(s)/trial(s) in thegiven context (e.g., p≤0.05/0.01). “Detectable” means measurablypresent/different using known detection tools/techniques. The acronym“DOS” (or “DoS”) means “detectable(ly) or significant(ly).”

Uncontradicted, any value here that is not accompanied by a unit ofmeasurement (e.g., a weight of 50 or a length of 20), any previouslyprovided unit for the same element/step or the same type of element/stepwill apply, or, in cases where no such disclosure exists, the unit mostcommonly used in association with such an element/step in the art willapply.

Uncontradicted, the terms “including,” “containing,” “comprising,” and“having” mean “including, but not limited to” or “including, withoutlimitation.” Uncontradicted, use of terms such as comprising andincluding regarding elements/steps means including any detectable numberor amount of an element or including any detectable performance of astep/number of steps (with or without other elements/steps).

For conciseness, description of an aspect “comprising” or “including” anelement, with respect to a collection/whole (e.g., a system, device, orcomposition), implicitly provides support for any detectableamount/number or ≥˜1%, ≥˜5%, ≥˜10%, ≥˜20%, ≥˜25%, ≥˜33%, ≥˜50%, ≥˜51%,≥˜66%, ≥˜75%, ≥˜90%, ≥˜95%, ≥˜99%, or ˜100% of the whole/collectionbeing made up of the element, or essentially all of the whole/collectionbeing made up of the element (i.e., that the collection consistsessentially of the referenced element). Similarly, a method described asincluding a step with respect to an effect/outcome implicitly providessupport for the referenced step providing ≥˜1%, ≥˜5%, ≥˜10%, ≥˜20%,≥˜25%, ≥˜33%, ≥˜50%, ≥˜51%, ≥˜66%, ≥˜75%, ≥˜90%, ≥˜95%, ≥˜99%, or ˜100%of the effect/outcome, representing ≥˜1%, ≥˜5%, ≥˜10%, ≥˜20%, ≥˜25%,≥˜33%, ≥˜50%, ≥˜51%, ≥˜66%, ≥˜75%, ≥˜90%, ≥˜95%, ≥˜99%, or ˜100% of thesteps/effort performed, or both. Explicit listing of percentages ofelements/steps in connection with aspects does not limit or contradictsuch implicit disclosure.

Uncontradicted, terms such as “comprising” when used in connection witha step of a method provide implicit support for performing the steponce, ≥2 times, or until an associated function/effect is achieved.

Uncontradicted, the term “one” means a single type, singleiteration/copy/thing, of a recited element or step, or both, which willbe clear from context. For example, the referent “one” used with acomponent of a composition can refer to one type of element (which maybe present in numerous copies, as in the case of an ingredient in acomposition), one unit of the element, or both. Similarly, “one”component, a “single” component, or the “only component” of a systemtypically means 1 type of element (which may be present in numerouscopies), 1 instance/unit of the element, or both. Further, “one” step ofa method typically means performing one type of action (step), oneiteration of a step, or both. Uncontradicted, a disclosure of “one”element provides support for both, but uncontradicted, any claim to any“one” element means one type of such an element (e.g., a component of acomposition/system).

The term “some” means ≥2 copies/instances or ≥5% of a listedcollection/whole is, or is made up of, an element. Regarding methods,some means ≥5% of an effect, effort, or both, is made up of or isattributable to a step (e.g., as in “some of the method is performed bystep Y”) or indicates a step is performed ≥2 times (e.g., as in “step Xis repeated some number of times”). “Predominately,” “most,” or“mostly,” means detectably >50% (e.g., mostly comprises, predominatelyincludes, etc., mean >50%) (e.g., a system that mostly includes elementX is composed of ≥50% of element X). The term “generally” means ≥75%(e.g., generally consists of, generally associated with, generallycomprises, etc., means ≥75%) (e.g., a method that generally consists ofstep X means that 75% of the effort or effect of the method isattributable to step X). “Substantially” or “nearly” means ≥95% (e.g.,nearly all, substantially consists of, etc., mean ≥95%) (e.g., acollection that nearly entirely is made up of element X means that atleast 95% of the elements in the collection are element X). Terms suchas “generally free” of an element or “generally lacking” an element meancomprising ≤˜25% of an element and terms such as “substantially free” ofan element mean comprising ≤˜5% of an element.

In certain embodiments describing API(s), excipient(s), or both presentin amounts of “at least” or “greater than” a given amount or, e.g.,present in amounts of “no more than” or “no greater than” or “less than”a given amount, the reader should interpret such disclosure asdisclosing, e.g., encompassing and explicitly including, such undefinedlow or high amount(s) ranging to the opposite amount (high or low) thatis maximally/minimally therapeutically effective, typically suitable, orboth. For example, use of the phrase “at least” (and similardescriptors) in connection with an amount of a component of aformulation or of an entire formulation/composition can be interpretedas at least the amount described but that is no more than a maximallysuitable or therapeutically effective amount (in the individual or in apopulation, such as determined in a clinical study). Similarly, phrasessuch as “less than” (and similar descriptors) an indicated amount can beinterpreted referring to an amount that is still suitable (including,where appropriate, no amount, e.g., 0 units of the indicated component)or therapeutically effective (e.g., an amount that results in a DOSresult in a significant number of individuals in a well-controlled andadequate study) but is less than the indicated amount.

Constituents herein are typically present in “effective amounts,” anduncontradicted, any described class/type of, e.g., excipient (oftenreferred to as a “component” herein—e.g., a “buffer component” mayinclude one or more buffers) or specific excipient, or, e.g., in certainaspects active pharmaceutical ingredient(s) (API(s)) is understood to bepresent in the associated composition/formulation in an effectiveamount, which generally means, in this context, an amount that iseffective for the described function(s) associated with theexcipient/API (it being understood that some excipient or APIcompound(s)/ingredient(s) exhibit more than one effect). E.g., atonicity agent will be understood to be present in acomposition/formulation in an amount that is effective to impart anindicated tonicity effect, a tonicity effect that is required forsuitability of the composition, or an effect that imparts a detectableor significant tonicity effect on a composition (with respect to acomparator composition lacking the compound(s)/ingredient(s)).

The phrase “substantially identical” may be used in certain contexts toreflect that tests that would be considered substantially identical bythose of skill in the art (not differing meaningfully in terms ofoutcome) or that component(s) or step(s) can achieve the same result ina similar way as a referenced set of component(s)/step(s) so as to notmeaningfully differ in intended result and manner of achieving such aresult. It will be appreciated that the phrase “substantially identical”in such contexts comprises the use of identical amounts, identicalformulations, and identical conditions, or, e.g., in other respects,composition(s) demonstrate an identical performance as a comparator.

Uncontradicted, any aspect described with respect to an optionallypresent element(s)/step(s) also provides implicit support forcorresponding aspect(s) in which one, some, most, generally all, nearlyall, essentially all, or all of such element(s) are lacking/step(s) notperformed, in respect of the relevant aspect. E.g., disclosure of asystem comprising element X implicitly also supports a system lackingelement X.

Uncontradicted, changes to tense or presentation of terms (e.g., using“comprises predominately” in place of “predominately comprises”) do notchange the meaning of the corresponding term/phrase.

Uncontradicted, all methods provided here can be performed in anysuitable order regardless of presentation (e.g., a method comprisingsteps A, B, and C, can be performed in the order C, B, and A; B and Aand C simultaneously, etc.). Uncontradicted, elements of a compositioncan be assembled in any suitable manner by any suitable method. Ingeneral, any methods and materials similar or equivalent to thosedescribed here can be used in the practice of embodiments.Uncontradicted, the use of ordinal numbers such as “first,” “second,”“third,” etc. is to distinguish respective elements rather than todenote a particular order of those elements.

Uncontradicted, any elements, steps, components, or features of aspectsand all variations thereof, etc., are within the scope of the invention.

Elements associated with a function can be described as “means for”performing a function in a composition/device/system or a “step for”performing a part of a method, and parts of this disclosure refer to“equivalents,” which means equivalents known in the art for achieving areferenced function associated with disclosed mean(s)/step(s). However,no element of this disclosure or claim should be interpreted as limitedto a “means-plus-function” construction unless such intent is clearlyindicated by the use of the terms “means for” or “step for.” Terms suchas “configured to” or “adapted to” do not indicate “means-plus-function”interpretation, but, rather, describe element(s)/step(s) configured to,designed to, selected to, or adapted to achieve a certain performance,characteristic, property, etc. using teachings provided here or in theart.

All references (e.g., publications, patent applications, and patents)cited herein are hereby incorporated by reference as if each referencewere individually and specifically indicated to be incorporated byreference and set forth in its entirety herein. Uncontradicted, anysuitable principles, methods, or elements of such references(collectively “teachings”) can be combined with or adapted to aspects.However, citation/incorporation of patent documents is limited to thetechnical disclosure thereof and does not reflect any view regarding thevalidity, patentability, etc., thereof. In the event of any conflictbetween this disclosure and the teachings of such documents, the contentof this disclosure controls regarding aspects of the invention. Numerousreferences are cited here to concisely incorporate known information andaid skilled persons in putting aspects into practice. While efforts havebeen made to include the most relevant references for such purposes,readers will understand that not every aspect of every cited referencewill apply to every aspect of the invention.

All original claims contained in this disclosure when filed areincorporated into this specification as if they were a part of thedescription.

Additional Terms, Concepts, and Acronyms

The following description of certain terms and acronyms is provided toassist readers in understanding the invention. Additional acronyms maybe only provided in other parts of this disclosure and acronyms that arewell known in the art may not be provided here.

Uncontradicted, any description of weight is percent weight/volume (“%w/v”).

Uncontradicted, the term “composition” as used herein, isinterchangeable with pharmaceutical formulation, liquid composition,liquid formulation, and formulation, and refers to preparationscomprising, e.g., a bimatoprost compound and a timolol compound in aform suitable for ophthalmic administration to a patient or subject. Attimes herein, the term “formulation” is used to describe a compositionwherein exemplary ranges of composition constituents are provided, and“composition” is used where specific composition constituents areprovided in specific exemplary amounts. Herein, uncontradicted, the term“constituent(s)” when referencing a composition or component of acomposition refers to a compound/agent contained in the composition orcomponent. A composition can have any suitable form, such as an ointmentor a solution. In aspects, a composition is a solution, a gel, or both.Uncontradicted, disclosure of a composition, formulation, and the like,provides implicit support for any of the various specific types ofcompositions described herein as if separately stated (e.g., disclosureof a composition or formulation should be understood to disclose “a gel,a solution, or other type of composition . . . ”).

The terms “treating,” “treatment,” and the like are generallyunderstood. Uncontradicted, terms such as “treating” or “treatment”herein refer to any suitable type of treatment, and typically encompassany approach for obtaining measurable or significant beneficial ordesired results in a subject's condition, including clinical results.Beneficial or desired clinical results can include, but are not limitedto, alleviation or amelioration of one or more symptoms or conditions,diminishment of the extent of a disease, stabilizing (e.g., notworsening) the state of the disease or condition, slowing or delayingthe progression of a disease or condition, amelioration or palliation ofthe disease state, diminishment of the reoccurrence of a disease orcondition, and, e.g., remission, whether partial or total, and whetherdetectable or undetectable. In other words, uncontradicted, “treatment”as used herein includes any cure, amelioration, or prevention of adisease. Treatment may prevent the disease from occurring; inhibit thedisease's spread; relieve the disease's symptoms (e.g., ocular pain,seeing halos around lights, red eye, very high intraocular pressure),fully or partially remove the disease's underlying cause, shorten adisease's duration, or do a combination of such effects. Readers willunderstand that each of the types of treatment described herein canrepresent separate and meaningfully different embodiments. Accordingly,the use of terms such as “treat” herein provide simultaneous implicitsupport for any of the particular forms of treatment described in thisparagraph or elsewhere in this disclosure (e.g., stabilizing acondition, reducing the severity of a condition, reducing the durationof a condition, treating one or more particular conditions, etc.).

Except where explicitly indicated or clearly indicated by context,“improved” herein means detectably or significantly “increased.” Inaspects, “improved” means detectably or significantly “reduced,” such aswith respect to the toxicity of a composition. Uncontradicted, termssuch as “enhanced,” “improved,” and the like are used synonymouslyherein.

“Pharmaceutical suitability”, “pharmaceutically suitable”,“ophthalmologically suitable” or “ophthalmological suitability” arephrases typically used to refer to compositions that are safe andeffective for pharmaceutical administration and application, andparticularly ophthalmological application(s), having sufficient potency,purity, strength, quality, and safety, stability, and tolerability, forpharmaceutical application, in cases specifically to the eye, as may bejudged by regulatory authority review, and as established by, e.g., oneor more well-controlled and adequate clinical studies performed incompliance with generally prevailing regulatory authority standards.Compositions described as “ophthalmologically suitable” should beinterpreted to mean suitable for ophthalmic delivery when provided in apotency, purity, strength, or quality making it safe for ophthalmic use.Components described as “ophthalmologically suitable” should beinterpreted in a similar manner. Uncontradicted, a description of“suitability” implicitly means that the referenced element, step, etc.,is ophthalmologically/pharmaceutically suitable or otherwise medicallysuitable (e.g., safe and effective and otherwise suitable, such astolerable in most, generally all, nearly all or essentially allrecipients in one or more studies, or otherwise suitable forapplications to the eye or treatment of eye conditions, as determined byproper nonclinical/clinical testing).

Excipients herein are typically present in “effective amounts,” anduncontradicted, any described class/type of excipient (often referred toas a “component” herein—e.g., a “buffer component” may include one ormore buffers) or specific excipient is understood to be present in theassociated composition/formulation in an effective amount, whichgenerally means, in this context, an amount that is effective for thedescribed function(s) associated with the excipient (it being understoodthat some excipient compound(s)/ingredient(s) exhibit more than oneeffect). E.g., a tonicity agent will be understood to be present in acomposition/formulation in an amount that is effective to impart anindicated tonicity effect, a tonicity effect that is required forsuitability of the composition, or an effect that imparts a detectableor significant tonicity effect on a composition (with respect to acomparator composition lacking the compound(s)/ingredient(s)).

Similarly, active pharmaceutical ingredients (APIs), e.g., PACs, BACs,or AGACs (if present), typically individually or collectively arepresent in effective amounts. Pharmaceutical efficacy is understood inthe art and, uncontradicted, such APIs can be effective in any one ormore suitable modalities/ways. For example, an effective amount of anAPI is an amount that can detectably or significantly treat one or moreaspects of a condition or disease (or, e.g., related symptom of such acondition or disease), such as may be established through one or morewell-controlled and adequate clinical studies, bioequivalence, or othersuitable means.

Aspects of the invention are described broadly and generically herein,as well as in narrower species and examples. Each of the narrowerspecies, examples, and subgeneric groupings falling within the genericdisclosure also form part of the invention. This includes the genericdescription of the invention with a proviso or negative limitationremoving one or more specific matters from the genus, regardless ofwhether or not the excised (specifically excluded) material isspecifically recited herein.

SUMMARY OF THE INVENTION

The inventions described and claimed herein have many attributes andaspects including, but not limited to, those set forth in, e.g.,described or referenced in, this Summary. This Summary of the Invention(“Summary”) is not intended to be all-inclusive, and the scope of theinvention is not limited to or by the aspects, features, elements, orembodiments provided in this Summary, which is included for illustrativepurposes only and not restriction. Any of the aspects described underthis section can be combined with any other aspect described in thissection or with any other aspect of this disclosure.

In aspects, disclosed herein are pharmaceutically acceptable andophthalmologically suitable compositions comprising a therapeuticallyeffective quantity of a prostaglandin analogue, such as, e.g.,bimatoprost, such as bimatoprost base, and a beta-adrenergic receptorantagonist, such as, e.g., timolol or ophthalmological acceptable saltthereof, e.g., timolol maleate. In certain aspects, the inventionprovides ophthalmic compositions comprising bimatoprost base and timololmaleate. In aspects, the invention provides a process of preparing suchcompositions and associated methods of their use.

In aspects, the invention provides pharmaceutically acceptable andophthalmologically suitable compositions comprising a therapeuticallyeffective quantity of a prostaglandin analogue, such as, e.g.,bimatoprost, e.g., bimatoprost base, and a beta-adrenergic receptorantagonist, such as, e.g., timolol or ophthalmological acceptable saltthereof, e.g., timolol maleate, wherein the composition is provided as aclear, aqueous solution or in the form of a gel, and, specifically,methods of their use in the treatment of one or more ocular conditionsor symptoms related thereto.

In certain specific aspects, the invention provides a pharmaceuticallyacceptable and ophthalmologically suitable composition for treating anocular condition in a mammalian eye comprising (1) about 0.005%w/v-about 0.02% w/v of a bimatoprost compound; (2) about 0.4% w/v-about0.8% w/v of a timolol compound; (3) about 0.003%-about 0.007% of aquaternary ammonium salt; and (4) about 0.25% w/v-about 2.5% w/v of apenetration enhancer component, wherein the ratio of the quaternaryammonium salt to the penetration enhancer component is about 1: about35-about 1: about 840, the ratio of the bimatoprost compound to thepenetration enhancer component is about 1: about 12.5-about 1: about500, the ratio of the timolol compound to the penetration enhancercomponent is between about 3.2: about 1-about 1: about 6.3, or anycombination of such ratios are present.

In certain specific aspects, the invention provides a pharmaceuticallyacceptable and ophthalmologically suitable composition in the form of agel comprising (1) about 0.005% w/v-about 0.02% w/v of a bimatoprostcompound; (2) about 0.4% w/v-about 0.8% w/v of a timolol compound; (3)about 0.003%-about 0.007% of a quaternary ammonium salt; and (4) about0.1% w/v-about 1% w/v of a viscosity enhancing component, wherein theratio of timolol compound to the viscosity enhancer component is about10: about 1 to about 1: about 10.

In aspects, the invention provides a pharmaceutically acceptable andophthalmologically suitable composition in the form of, e.g., a solutionor a gel for treating an ocular condition, e.g., elevated intraocularpressure, glaucoma (e.g., open-angle glaucoma), or both, in a mammalianeye comprising (1) about 0.005% w/v-about 0.02% w/v of a bimatoprostcompound; (2) about 0.4% w/v-about 0.8% w/v of a timolol compound; (3)about 0.003%-about 0.007% of a quaternary ammonium salt; and (4) about0.25% w/v-about 2.5% w/v of a penetration enhancer component. In certainaspects, the inclusion of a penetration enhancer component is optional.In aspects, the inclusion of a penetration enhancer is excluded incertain compositions, such as, e.g., certain embodiments of compositionsprovided as a gel.

In certain aspects, the invention provides pharmaceutically acceptableand ophthalmologically suitable gel compositions for treating an ocularcondition, such as, e.g., elevated intraocular pressure, glaucoma (e.g.,open-angle glaucoma), or both, in a mammalian eye comprising (1) about0.005% w/v-about 0.02% w/v of a bimatoprost compound; (2) about 0.4%w/v-about 0.8% w/v of a timolol compound; (3) about 0.003%-about 0.007%of a quaternary ammonium salt, and (4) about 0.1% w/v-about 1% of aviscosity enhancing component, wherein the viscosity of the compositiondetectably or significantly increases (a) upon exposure to theenvironment of the mammalian eye to which it is administered, (b) uponexposure to temperatures of at least about 32 degrees Celsius (° C.),(c) upon exposure to an environment having an ionic strength detectablyor significantly greater than that of one or more gelling agents presentin the composition (e.g., gellan gum), (d) exposure to an environmenthaving a pH of greater than about 6.2, or (e) any combination of(a)-(d), over the viscosity of the composition while stored prior toadministration at a temperature of between about 15° C. to about 25° C.+/−2° C.).

In aspects, compositions provided by the invention are characterized byone or more ratios of components or constituents therein. In aspects,the invention provides compositions wherein the ratio of a quaternaryammonium salt component of a composition to a penetration enhancercomponent of a composition (e.g., when such a penetration enhancercomponent is present) is about 1:35-about 1:840. In aspects, theinvention provides compositions wherein the ratio of the bimatoprostcompound to a penetration enhancer component of a composition is about1:12.5-about 1:500. In aspects, the invention provides compositionswherein the ratio of the timolol compound to a penetration enhancercomponent is between about 3.2:1-1:6.3. In aspects, the inventionprovides compositions wherein the ratio of the total amount of APIconsisting of the bimatoprost compound and the timolol compound to apenetration enhancement component of a composition is about 3.2:1 toabout 1:6.3.

In aspects, the invention provides such a composition wherein thecomposition is characterized by one or more ratios of components orconstituents therein to a viscosity enhancer component of thecomposition. In aspects, the invention provides compositions wherein theratio of the bimatoprost compound, e.g., bimatoprost base, to theviscosity enhancer component is about 1:2 to about 1:1000. In aspects,the invention provides compositions wherein the ratio of timololcompound, e.g., a salt of timolol, e.g., timolol maleate, to theviscosity enhancer component is about 10:1 to about 1:10. In aspects,the invention provides compositions wherein the ratio of the totalamount of API consisting of the bimatoprost compound, e.g., bimatoprostbase, and the timolol compound, e.g., salt of timolol, e.g., timololmaleate, to the viscosity enhancer component is about 10:1 to about1:10.

In aspects, compositions provided by the invention are stable whenstored under controlled room temperature conditions (e.g., temperatureof about 15° C. to 25° C. +/−2° C.) for a period of at least about 1months, such as, e.g., at least about 3 months, at least about 6 months,at least about 9 months, at least about 12 months, at least about 18months, at least about 24 months, at least about 28 months, at leastabout 32 months, or, e.g., at least about 36 months.

In aspects, the invention provides methods of treatment using suchcompositions, such as methods of treating elevated intraocular pressure,glaucoma (e.g., open-angle glaucoma), or both. In aspects, the inventionprovides such methods wherein application of the methods results in animprovement in the target indication, e.g., a reduction in elevatedintraocular pressure, which was unsatisfactorily responsive to priortreatment of the target indication with a topical beta-blockeradministered alone, a prostaglandin analogue administered alone, orboth.

In aspects, the invention provides methods of treatment using suchcompositions, such as methods of treating elevated intraocular pressure,glaucoma (e.g., open-angle glaucoma), or both. In aspects, applicationof such method(s) is clinically demonstrated to (1) be as effective ordetectably or significantly more effective than treatment of the same orat least essentially the same, generally the same, or the same conditionwith about the same amount of the product approved as European MedicinesAgency product number EMEA/H/C/000668 (presently sold under thetrademark “GANFORT®”) (having first received market approval in 2006)for the same or similar indication (e.g., reducing IOP) and for at leastsubstantially the same administration period; (2) result in the user oran average population of users experiencing a reduction in frequency ofadverse events (e.g., negative side effects) than those reported asadverse events (e.g., negative side effects) for the product approved asEuropean Medicines Agency product number EMEA/H/C/000668 (GANFORT®)(having first received market approval in 2006); (3) result in apopulation of treated subjects, on average, maintaining a longer courseof therapy than the course of therapy tolerated by a comparablepopulation of treated subjects treated with the product approved asEuropean Medicines Agency product number EMEA/H/C/000668 (GANFORT®)(having first received market approval in 2006) for the same or similarindication; or (4) any combination of (1), (2), and (3).

In one specific aspect, the invention provides a method of treatingelevated intraocular pressure, glaucoma, or both, in a mammalian eye,the method comprising administration of an effective amount of acomposition comprising (1) about 0.005% w/v-about 0.02% w/v of abimatoprost compound; (2) about 0.4% w/v-about 0.8% w/v of a timololcompound; (3) about 0.003%-about 0.007% of a quaternary ammonium salt;and (4) about 0.25% w/v-about 2.5% w/v of a penetration enhancercomponent, wherein the composition is further characterized by (a) theratio of the quaternary ammonium salt to the penetration enhancercomponent is between about 1:35-about 1:840; (b) the ratio of thebimatoprost compound to the penetration enhancer component is about1:12.5-about 1:500; (c) the ratio of the timolol compound to thepenetration enhancer component is between about 3.2:1-1:6.3; or (d) anycombination of (a) the ratio of the quaternary ammonium salt to thepenetration enhancer component is between about 1:35-about 1:840; (b)the ratio of the bimatoprost compound to the penetration enhancercomponent is about 1:12.5-about 1:500; and (c) the ratio of the timololcompound to the penetration enhancer component is between about3.2:1-1:6.3 are true.

In certain further aspects, the invention provides a method of treatingelevated intraocular pressure, glaucoma, or both, in a mammalian eye,the method comprising administration of an effective amount of acomposition in the form of a gel comprising (1) about 0.005% w/v-about0.02% w/v of a bimatoprost compound; (2) about 0.4% w/v-about 0.8% w/vof a timolol compound; (3) about 0.003%-about 0.007% of a quaternaryammonium salt; and (4) about 0.1% w/v-about 1% w/v of a viscosityenhancing component, wherein the ratio of timolol compound to theviscosity enhancer component is about 10: about 1 to about 1: about 10.

In aspects, the invention provides methods of manufacturing compositionsdescribed in this Summary section, as well as kits for distributing andstoring such compositions.

Exemplary Aspects of the Invention

The following is a non-limiting list of exemplary aspects of theinvention, which illustrates embodiments of the invention in a summaryform to aid readers in quickly understanding the overall scope of theinvention. Similar to patent claims, listed aspects described in theparagraphs of this section may refer to (depend on/from) one or moreother paragraphs. Readers will understand that such references mean thatthe features/characteristics or steps of such referenced aspects areincorporated into/combined with the referring aspect. E.g., if an aspectin a paragraph (e.g., a paragraph indicated by text at the end of theparagraph as aspect 2) refers to another aspect by one or more aspectnumbers (e.g., aspect 1 or “any one of aspects 1-3”), it will beunderstood to include the elements, steps, or characteristics of suchreferenced aspects (e.g., aspect 1) in addition to those of the aspectin which the reference is made (e.g., if aspect 2 refers to aspect 1, itprovides a description of a composition, method, system, device, etc.,including the features of both aspect 1 and aspect 2).

Lists of aspects describing specific exemplary embodiments of theinvention are sometimes employed for aiding the reader in understandingthe invention. Such aspects can, within them, reference other exemplaryaspects, either individually or as groups of aspects (e.g., viareference to a range within a list of numbered aspects when such aspectsare provided as a numbered list). Reference to ranges of aspects shouldbe interpreted as referencing all such aspects individually, each asunique embodiments of the invention, and in combination with one anotheras unique embodiment(s) of the invention, according to the presentationprovided of such aspects unless such an aspect within such a referencedrange is either contradictory or non-sensical. If contradicted,reference to the contradictory aspect should be excluded.

In one aspect, the invention provides a pharmaceutically acceptable andophthalmologically suitable composition for treating an ocular conditionin a mammalian eye comprising (1) about 0.005% w/v-about 0.02% w/v of abimatoprost compound; (2) about 0.4% w/v-about 0.8% w/v of a timololcompound; (3) about 0.003%-about 0.007% of a quaternary ammonium salt;and (4) about 0.25% w/v-about 2.5% w/v of a penetration enhancercomponent, wherein the ratio of the quaternary ammonium salt to thepenetration enhancer component is about 1:35-about 1:840 (aspect 1).

In one aspect, the invention provides the composition of aspect 1,wherein (1) the ratio of the bimatoprost compound to the penetrationenhancer component is about 1:12.5-about 1:500; (2) the ratio of thetimolol compound to the penetration enhancer component is between about3.2:1-1:6.3 (e.g., ˜3.2:1-˜1:6.25); or (3) both (1) and (2) are true(aspect 2).

In one aspect, the invention provides a pharmaceutically acceptable andophthalmologically suitable composition for treating an ocular conditionin a mammalian eye comprising (1) about 0.005% w/v-about 0.02% w/v of abimatoprost compound; (2) about 0.4% w/v-about 0.8% w/v of a timololcompound; (3) about 0.003%-about 0.007% of a quaternary ammonium salt;and (4) about 0.25% w/v-about 2.5% w/v of a penetration enhancercomponent, wherein the ratio of the bimatoprost compound to thepenetration enhancer component is about 1:12.5-about 1:500 (aspect 3).

In one aspect, the invention provides the composition of aspect 3,wherein (1) the ratio of the quaternary ammonium salt to the penetrationenhancer component is about 1:35-about 1:840, (2) the ratio of thetimolol compound to the penetration enhancer component is between about3.2:1-1:6.3 (e.g., ˜3.2:1-˜1:6.25), or (3) both (1) and (2) are true(aspect 4)

In one aspect, the invention provides a pharmaceutically acceptable andophthalmologically suitable composition for treating an ocular conditionin a mammalian eye comprising (1) about 0.005% w/v-about 0.02% w/v of abimatoprost compound; (2) about 0.4% w/v-about 0.8% w/v of a timololcompound; (3) about 0.003%-about 0.007% of a quaternary ammonium salt;and (4) about 0.25% w/v-about 2.5% w/v of a penetration enhancercomponent, wherein the ratio of the timolol compound to the penetrationenhancer component is between about 3.2:1-1:6.3 (e.g., ˜3.2:1-˜1:6.25)(aspect 5).

In one aspect, the invention provides the composition of aspect 5,wherein (1) the ratio of the bimatoprost compound to the penetrationenhancer component is about 1:12.5-about 1:500, (2) the ratio of thequaternary ammonium salt to the penetration enhancer component is about1:35-about 1:840, or (3) both (1) and (2) are true (aspect 6).

In aspects, the invention provides the composition of any one or more ofaspects 1-6, wherein the penetration enhancer component comprises one ormore constituents which provides both detectably or significantlyincreased penetration of the bimatoprost compound, the timolol compound,or both the bimatoprost and timolol compounds into corneal tissue, andwherein the penetration enhancer component comprises one or more of (1)a protein/peptide constituent, (2) a non-protein/peptide constituent, or(3) a combination of (1) and (2) (aspect 7).

In aspects, the invention provides the composition of any one or both ofaspect 1 or aspect 7, wherein the penetration enhancer componentcomprises at least one constituent which provides detectable orsignificant activity as two or more of a penetration enhancer, asolubilizer, a demulcent, a buffer, a tonicity agent, a thickener, achelator, a pH adjusting agent, a preservative, or a carrier (aspect 8).

In aspects, the invention provides the composition of any one or more ofaspects 1-8, wherein the penetration enhancer component comprises atleast one constituent which provides detectable or significant activityas a penetration enhancer, a solubilizer, a demulcent, or anycombination of two or more thereof (aspect 9).

In aspects, the invention provides the composition of any one or more ofaspects 1-9, wherein the penetration enhancer component comprises atleast one constituent which provides detectable or significant activityas a penetration enhancer, a solubilizer, and a demulcent (aspect 10).

In aspects, the invention provides the composition of any one or more ofaspects 1-5, wherein the penetration enhancer component comprises atleast one constituent characterizable as a non-ionic surfactant havingan HLB value of at least about 14.5, e.g., at least about 16.5 (aspect11).

In aspects, the invention provides the composition of any one or more ofaspects 1-11, wherein the penetration enhancer component comprises oneor more of one or more polyoxyethylene sorbitan fatty acid ester(s),tocopheryl polyethylene glycol succinate (TPGS), poly-arginine, orpolyserine (aspect 12).

In aspects, the invention provides the composition of any one or more ofaspects 1-11, wherein the penetration enhancer component comprises oneor more constituents characterizable as a protein/peptide (aspect 13).

In aspects, the invention provides the composition of any one or more ofaspects 1-13, wherein the penetration enhancer component comprisespoly-arginine (aspect 14).

In aspects, the invention provides the composition of any one or more ofaspects 1-14, wherein the penetration enhancer component comprisespoly-serine (aspect 15).

In aspects, the invention provides the composition of any one or more ofaspects 1-15, wherein the penetration enhancer component comprises oneor more constituents characterizable as a non-protein/peptide (aspect16).

In aspects, the invention provides the composition of any one or more ofaspects 1-16, wherein the penetration enhancer component comprises oneor more compounds selected from a group consisting of polyethylenesorbitan fatty acid esters, tocopherol polyethylene glycol succinate(TPGS), and polyoxyl hydrogenated castor oil (aspect 17).

In aspects, the invention provides the composition of any one or more ofaspects 1-17, wherein the penetration enhancer component comprises apolyethylene sorbitan fatty acid ester selected from the groupconsisting of polyoxyethylene sorbitan laurate (polysorbate 20),polyoxyethylene sorbitan palmitate (polysorbate 40), a polyoxyethylenesorbitan stearate (polysorbate 60), a polyoxyethylene sorbitan tristearate (polysorbate 65), or a polyoxyethylene sorbitanoleate/polyoxyethylene sorbitan mono-oleate ester (e.g., polysorbate80), or a combination thereof (aspect 18).

In aspects, the invention provides the composition of any one or more ofaspects 1-18, wherein the penetration enhancer component comprisespolysorbate 20, polysorbate 80, or a combination of polysorbate 20 andpolysorbate 80 (aspect 19).

In aspects, the invention provides the composition of any one or more ofaspects 1-19, wherein the penetration enhancer component comprisespolysorbate 20 (aspect 20).

In aspects, the invention provides the composition of any one or more ofaspects 1-20, wherein the penetration enhancer component comprisespolysorbate 80 (aspect 21).

In aspects, the invention provides the composition of any one or more ofaspects 1-21, wherein the penetration enhancer component comprises TPGS(aspect 22).

In aspects, the invention provides the composition of any one or more ofaspects 1-22, wherein the penetration enhancer component comprises aconstituent characterizable as a polyoxyl hydrogenated castor oil(aspect 23).

In aspects, the invention provides the composition of any one or more ofaspects 1-23, wherein the penetration enhancer component comprisespolyoxyl 35 castor oil (cremophor EL) (aspect 24).

In aspects, the invention provides the composition of any one or more ofaspects 1-24, wherein the penetration enhancer component is present inan amount representing about 0.5% w/v-about 2% w/v of the composition(aspect 25).

In aspects, the invention provides the composition of any one or more ofaspects 1-25, wherein the penetration enhancer component is present inan amount representing about 0.7% w/v-about 1.5% w/v of the composition(aspect 26).

In aspects, the invention provides the composition of any one or more ofaspects 1-26, wherein the penetration enhancer component is present inan amount of between about 0.8% w/v-about 1.1% w/v of the composition(aspect 27).

In aspects, the invention provides the composition of any one or more ofaspects 1-27, wherein the penetration enhancer component is present inan amount representing about 1% w/v of the composition (aspect 28).

In aspects, the invention provides the composition of any one or more ofaspects 1-28, wherein the penetration enhancer component is present inan amount representing about 1.005% w/v of the composition (aspect 29).

In aspects, the invention provides the composition of any one or more ofaspects 1-29, wherein the bimatoprost compound is bimatoprost (aspect30).

In aspects, the invention provides the composition of any one or more ofaspects 1-30, wherein the bimatoprost compound is present in an amountrepresenting about 0.007% w/v-about 0.02% w/v of the composition (aspect31)

In aspects, the invention provides the composition of any one or more ofaspects 1-31, wherein the bimatoprost compound is present in an amountrepresenting about 0.009% w/v-about 0.015% w/v of the composition(aspect 32).

In aspects, the invention provides the composition of any one or more ofaspects 1-32, wherein the bimatoprost compound is present in an amountrepresenting about 0.01% w/v of the composition (aspect 33).

In aspects, the invention provides the composition of any one or more ofaspects 1-33, wherein the timolol compound is present as anophthalmologically suitable salt of timolol (aspect 34).

In aspects, the invention provides the composition of any one or more ofaspects 1-34, wherein the ophthalmologically suitable salt of timolol istimolol maleate (aspect 35).

In aspects, the invention provides the composition of any one or more ofaspects 1-35, wherein the composition comprises timolol maleate in anamount representing about 0.5% w/v-about 0.7% w/v of the composition(aspect 36).

In aspects, the invention provides the composition of any one or more ofaspects 1-36, wherein the composition comprises timolol maleate in anamount representing about 0.6% w/v-about 0.7% w/v of the composition(aspect 37).

In aspects, the invention provides the composition of any one or more ofaspects 1-37, wherein the composition comprises timolol maleate in anamount representing about 0.68% w/v (equivalent to about 0.5% timolol)of the composition (aspect 38).

In aspects, the invention provides the composition of any one or more ofaspects 1-38, wherein the quaternary ammonium salt is a benzalkoniumchloride compound (aspect 39).

In aspects, the invention provides the composition of any one or more ofaspects 1-39, wherein the benzalkonium chloride compound is benzalkoniumchloride (aspect 40).

In aspects, the invention provides the composition of any one or more ofaspects 1-40, wherein the composition comprises benzalkonium chloride inan amount representing about 0.004% w/v-about 0.006% w/v of thecomposition (aspect 41).

In aspects, the invention provides the composition of any one or more ofaspects 1-41, wherein the composition comprises benzalkonium chloride inan amount representing about 0.004% w/v-about 0.005% w/v of thecomposition (aspect 42).

In aspects, the invention provides the composition of any one or more ofaspects 1-42, wherein the composition comprises benzalkonium chloride inan amount representing about 0.005% w/v of the composition (aspect 43).

In aspects, the invention provides the composition of any one or more ofaspects 1-43, wherein the composition comprises a ratio of quaternaryammonium salt, e.g., benzalkonium chloride, to penetration enhancercomponent of about 1:100 to about 1:300 (aspect 44).

In aspects, the invention provides the composition of any one or more ofaspects 1-44, wherein the ratio of quaternary ammonium salt, e.g.,benzalkonium chloride, to penetration enhancer component is about 1:200(aspect 45).

In aspects, the invention provides the composition of any one or more ofaspects 1-45, wherein the ratio of the bimatoprost compound to thetimolol compound is about 1:20 to about 1:160 (aspect 46).

In aspects, the invention provides the composition of any one or more ofaspects 1-46, wherein the ratio of the bimatoprost compound to thetimolol compound is about 1:50 to about 1:100 (aspect 47).

In aspects, the invention provides the composition of any one or more ofaspects 1-47, wherein the ratio of the bimatoprost compound to thetimolol compound is about 1:68 (aspect 48).

In aspects, the invention provides the composition of any one or more ofaspects 1-48, wherein the ratio of the bimatoprost compound to thequaternary ammonium salt, e.g., benzalkonium chloride, is about 6.7:1 toabout 1:1.4 (aspect 49).

In aspects, the invention provides the composition of any one or more ofaspects 1-49, wherein the ratio of the bimatoprost compound to thequaternary ammonium salt, e.g., benzalkonium chloride, is about 5:1 toabout 1:1 (aspect 50).

In aspects, the invention provides the composition of any one or more ofaspects 1-50, wherein the ratio of the bimatoprost compound to thequaternary ammonium salt, e.g., benzalkonium chloride, is about 2:1(aspect 51).

In aspects, the invention provides the composition of any one or more ofaspects 1-51, wherein the ratio of the bimatoprost compound to thepenetration enhancer component is about 1:12.5 to about 1:500 (aspect52).

In aspects, the invention provides the composition of any one or more ofaspects 1-52, wherein the ratio of the bimatoprost compound to thepenetration enhancer component is about 1:20 to about 1:200 (aspect 53).

In aspects, the invention provides the composition of any one or more ofaspects 1-53, wherein the ratio of the bimatoprost compound to thepenetration enhancer component is about 1:100 (aspect 54).

In aspects, the invention provides the composition of any one or more ofaspects 1-54, wherein the ratio of the timolol compound to thequaternary ammonium salt, e.g., benzalkonium chloride, is about 57.1:1to about 266.7:1 (aspect 55).

In aspects, the invention provides the composition of any one or more ofaspects 1-55, wherein the ratio of the timolol compound to thequaternary ammonium salt, e.g., benzalkonium chloride, is about 90:1 toabout 170:1 (aspect 56).

In aspects, the invention provides the composition of any one or more ofaspects 1-56, wherein the ratio of the timolol compound to thequaternary ammonium salt, e.g., benzalkonium chloride, is about 136:1(aspect 57).

In aspects, the invention provides the composition of any one or more ofaspects 1-57, wherein the ratio of the timolol compound to thepenetration enhancer component is about 3.2:1 to about 1:6.3 (e.g.,˜3.2:1-˜1:6.25) (aspect 58).

In aspects, the invention provides the composition of any one or more ofaspects 1-58, wherein the ratio of the timolol compound to thepenetration enhancer component is about 2:1 to about 1:3 (aspect 59).

In aspects, the invention provides the composition of any one or more ofaspects 1-59, wherein the ratio of the timolol compound to thepenetration enhancer component is about 1:1.47 (aspect 60).

In aspects, the invention provides the composition of any one or more ofaspects 1-60, wherein the ratio of the total amount of API consisting ofthe bimatoprost compound and the timolol compound to the quaternaryammonium salt, e.g., benzalkonium chloride, is about 57.9:1 to about273.3:1 (aspect 61).

In aspects, the invention provides the composition of any one or more ofaspects 1-61, wherein the ratio of the total amount of API consisting ofthe bimatoprost compound and the timolol compound to the quaternaryammonium salt, e.g., benzalkonium chloride, is about 100:1 to about150:1 (aspect 62).

In aspects, the invention provides the composition of any one or more ofaspects 1-62, wherein the ratio of the total amount of API consisting ofthe bimatoprost compound and the timolol compound to the quaternaryammonium salt, e.g., benzalkonium chloride, is about 138:1 (aspect 63).

In aspects, the invention provides the composition of any one or more ofaspects 1-63, wherein the ratio of the total amount of API consisting ofthe bimatoprost compound and the timolol compound to the penetrationenhancer component is about 3.28:1 to about 1:6.17 (aspect 64).

In aspects, the invention provides the composition of any one or more ofaspects 1-64, wherein the ratio of the total amount of API consisting ofthe bimatoprost compound and the timolol compound to the penetrationenhancer component is about 2:1-about 1:2 (aspect 65).

In aspects, the invention provides the composition of any one or more ofaspects 1-65, wherein the ratio of the total amount of API consisting ofthe bimatoprost compound and the timolol compound to the penetrationenhancer component is about 1:1.45 (aspect 66).

In aspects, the invention provides the composition of any one or more ofaspects 1-66, wherein the composition further comprises one or moreexcipients (aspect 67).

In aspects, the invention provides the composition of any one or more ofaspects 1-67, wherein the composition further comprises one or moreexcipients present in the composition as a constituent of a one or morecomponent(s) selected from the group consisting of a chelationcomponent, a tonicity component, a preservation component, asolubilization component, a buffer component, a pH-adjusting component,and a carrier component (aspect 68).

In aspects, the invention provides the composition of any one or more ofaspects 1-68, wherein the composition comprises a solubilizationcomponent comprising one or more constituents capable detectably orsignificantly increasing the solubilization of the bimatoprost compound,the timolol compound, or both the bimatoprost and timolol compounds(aspect 69).

In aspects, the invention provides the composition of any one or more ofaspects 1-69, wherein the composition comprises a solubilizationcomponent comprising one or more constituents distinctly different fromany compound providing detectably or significantly enhanced penetrationof the bimatoprost compound, the timolol compound, or both thebimatoprost and the timolol compounds (aspect 70).

In aspects, the invention provides the composition of any one or more ofaspects 1-70, wherein the composition comprises a solubilizationcomponent and wherein a constituent of the solubilization component istromethamine (tris) (aspect 71).

In aspects, the invention provides the composition of any one or more ofaspects 1-71, wherein the composition comprises tromethamine (tris) inan amount representing about 0.005% w/v-about 0.5% w/v of thecomposition (aspect 72).

In aspects, the invention provides the composition of any one or more ofaspects 1-72, wherein the composition comprises tromethamine (tris) inan amount representing about 0.01% w/v-about 0.3% w/v of the composition(aspect 73).

In aspects, the invention provides the composition of any one or more ofaspects 1-73, wherein the composition comprises tromethamine (tris) inan amount representing about 0.1% w/v-about 0.2% w/v of the composition(aspect 74).

In aspects, the invention provides the composition of any one or more ofaspects 1-74, wherein the composition comprises sesame seed oil or oilshaving similar compositions and functional characteristics suitable forophthalmic use (aspect 75).

In aspects, the invention provides the composition of any one or more ofaspects 1-75, wherein the composition comprises a solubilizationcomponent, and wherein the solubilization component comprises one ormore constituents which are also constituents of the penetrationenhancer component, such that the one or more constituents provides both(1) detectably or significantly increased penetration of the bimatoprostcompound, the timolol compound, or both the bimatoprost compound and thetimolol compound into corneal tissue, and (2) detectably orsignificantly increased solubilization of the bimatoprost compound, thetimolol compound, or both the bimatoprost compound and the timololcompound (aspect 76).

In aspects, the invention provides the composition of aspect 76, whereinthe composition comprises a solubilization component, and wherein thesolubilization component comprises any one or more of the constituentsdescribed in any one or more of aspects 8-29 (aspect 77).

In aspects, the invention provides the composition of any one or more ofaspects 1-77, wherein the total amount of any constituent(s) of thepenetration enhancer component, the solubilization component, or boththe penetration enhancer component and the solubilization component inthe composition represents about 0.1% w/v-about 5% w/v of thecomposition (aspect 78).

In aspects, the invention provides the composition of any one or more ofaspects 1-78, wherein the composition comprises a tonicity componentcomprising one or more constituents which provides a detectable orsignificant impact on the osmolality of the composition (aspect 79).

In aspects, the invention provides the composition of any one or more ofaspects 1-79, wherein the composition comprises a tonicity component andthe tonicity component comprises one or more constituents present in anamount sufficient to establish the osmolality of the composition atbetween about 280 mOsm/Kg-about 370 mOsm/Kg (aspect 80).

In aspects, the invention provides the composition of any one or more ofaspects 1-80, wherein the composition comprises a tonicity component andthe tonicity component is present in the composition in an amountrepresenting about 0.005% w/v-about 1% w/v of the composition (aspect81).

In aspects, the invention provides the composition of any one or more ofaspects 1-81, wherein the composition comprises a tonicity component andthe tonicity component comprises sodium chloride (aspect 82).

In aspects, the invention provides the composition of any one or more ofaspects 1-82, wherein the composition comprises sodium chloride in anamount representing about 0.5% w/v-about 1% w/v of the composition(aspect 83).

In aspects, the invention provides the composition of any one or more ofaspects 1-83, wherein the composition comprises sodium chloride in anamount representing about 0.7% w/v-about 0.9% w/v of the composition(aspect 84).

In aspects, the invention provides the composition of any one or more ofaspects 1-84, wherein the composition comprises sodium chloride in anamount representing about 0.8% w/v of the composition (aspect 85).

In aspects, the invention provides the composition of any one or more ofaspects 1-85, wherein the composition comprises a tonicity component andwherein the tonicity component does not comprise sodium chloride (aspect86).

In aspects, the invention provides the composition of any one or more ofaspects 1-86, wherein the composition comprises a tonicity component andwherein the tonicity component comprises mannitol (aspect 87).

In aspects, the invention provides the composition of any one or more ofaspects 1-87, wherein the composition comprises mannitol in an amountrepresenting about 2% w/v-about 6% w/v of the composition (aspect 88).

In aspects, the invention provides the composition of any one or more ofaspects 1-88, wherein the composition comprises mannitol in an amountrepresenting about 3% w/v-about 5% w/v of the composition (aspect 89).

In aspects, the invention provides the composition of any one or more ofaspects 1-89, wherein the composition comprises mannitol in an amountrepresenting about 4% w/v of the composition (aspect 90).

In aspects, the invention provides the composition of any one or more ofaspects 1-90, wherein the composition comprises mannitol in an amountrepresenting about 4.05% w/v of the composition (aspect 91).

In aspects, the invention provides the composition of any one or more ofaspects 1-91, wherein the composition does not comprise mannitol (aspect92).

In aspects, the invention provides the composition of any one or more ofaspects 1-92, wherein the composition comprises a buffer componentcapable of maintaining the pH of the composition at about 6.2-about 7,or, e.g., about 6.9-about 7.5 (aspect 93).

In aspects, the invention provides the composition of any one or more ofaspects 1-93, wherein the composition does not comprise a buffercomponent (aspect 94).

In aspects, the invention provides the composition of any one or more ofaspects 1-94, wherein the composition comprises a buffer componentcomprising at least one buffer component constituent (aspect 95).

In aspects, the invention provides the composition of any one or more ofaspects 1-95, wherein the composition comprises a buffer componentcomprising at least two buffer component constituents (aspect 96).

In aspects, the invention provides the composition of any one or more ofaspects 1-96, wherein the composition comprises a buffer componentcomprising a phosphate buffer constituent, a citrate buffer constituent,or both phosphate buffer and citrate buffer constituents (aspect 97).

In aspects, the invention provides the composition of any one or more ofaspects 1-97, wherein the composition comprises a buffer componentcomprising a phosphate buffer in an amount representing about 0.1%w/v-about 0.4% w/v of the composition (aspect 98).

In aspects, the invention provides the composition of any one or more ofaspects 1-98, wherein the composition comprises a buffer componentcomprising a phosphate buffer in an amount representing about 0.15%w/v-about 0.3% w/v of the composition (aspect 99).

In aspects, the invention provides the composition of any one or more ofaspects 1-99, wherein the composition comprises a buffer componentcomprising a phosphate buffer in an amount representing about 0.2%w/v-about 0.3% w/v of the composition (aspect 100).

In aspects, the invention provides the composition of any one or more ofaspects 1-100, wherein the composition comprises a buffer componentcomprising a phosphate buffer in an amount representing 0.268% w/v ofthe composition (aspect 101).

In aspects, the invention provides the composition of any one or more ofaspects 1-101, wherein the composition comprises a buffer componentcomprising dibasic sodium phosphate (aspect 102).

In aspects, the invention provides the composition of any one or more ofaspects 1-102, wherein the composition comprises a buffer componentcomprising a citrate buffer in an amount representing about 0.005%w/v-about 0.03% w/v of the composition (aspect 103).

In aspects, the invention provides the composition of any one or more ofaspects 1-103, wherein the composition comprises a buffer componentcomprising a citrate buffer in an amount representing about 0.009%w/v-about 0.02% w/v of the composition (aspect 104).

In aspects, the invention provides the composition of any one or more ofaspects 1-104, wherein the composition comprises a buffer componentcomprising a citrate buffer in an amount representing about 0.01%w/v-about 0.02% w/v of the composition (aspect 105).

In aspects, the invention provides the composition of any one or more ofaspects 1-105, wherein the composition comprises a buffer componentcomprising a citrate buffer in an amount representing about 0.014% w/vof the composition (aspect 106).

In aspects, the invention provides the composition of any one or more ofaspects 1-106, wherein the composition comprises a buffer componentcomprising citric acid monohydrate (aspect 107).

In aspects, the invention provides the composition of any one or more ofaspects 1-107, wherein the composition comprises a buffer componentcomprising a phosphate buffer in an amount of about 0.1% w/v-about 0.4%w/v of the composition and citrate buffer in an amount of about 0.005%w/v-about 0.03% w/v of the composition (aspect 108).

In aspects, the invention provides the composition of any one or more ofaspects 1-108, wherein the composition comprises a buffer componentcomprising a phosphate buffer in an amount of about 0.2% w/v-about 0.3%w/v of the composition and citrate buffer in an amount of about 0.01%w/v-about 0.02% w/v of the composition (aspect 109).

In aspects, the invention provides the composition of any one or more ofaspects 1-109, wherein the composition comprises a buffer componentcomprising a phosphate buffer in an amount of about 0.268% w/v of thecomposition and citrate buffer in an amount of about 0.014% w/v of thecomposition (aspect 110).

In aspects, the invention provides the composition of any one or more ofaspects 1-110, wherein the composition comprises a viscosity enhancercomponent which detectably or significantly increases the viscosity ofthe composition (1) upon exposure to the environment of the mammalianeye to which it is administered, (2) upon exposure to temperatures of atleast about 32 degrees Celsius (° C.), (3) upon exposure to anenvironment having an ionic strength detectably or significantly greaterthan that of one or more gelling agents present in the composition(e.g., gellan gum), (4) exposure to an environment having a pH ofgreater than about 6.2, or (5) any combination of (1)-(4), over theviscosity of the composition while stored prior to administration at atemperature of between about 15° C. to about 25° C. +/−2° C.) (aspect111).

In aspects, the invention provides the composition of any one or more ofaspects 1-111, wherein the composition does not comprise a viscosityenhancer component (aspect 112).

In aspects, the invention provides the composition of any one or more ofaspects 1-112, wherein the composition comprises gellan gum (aspect113).

In aspects, the invention provides the composition of any one or more ofaspects 1-113, wherein the composition comprises gellan gum in an amountrepresenting about 0.4% w/v-about 0.8% w/v of the composition (aspect114).

In aspects, the invention provides the composition of any one or more ofaspects 1-114, wherein the composition comprises gellan gum in an amountrepresenting about 0.5% w/v-about 0.7% w/v of the composition (aspect115).

In aspects, the invention provides the composition of any one or more ofaspects 1-115, wherein the composition comprises gellan gum in an amountrepresenting about 0.6% w/v of the composition (aspect 116).

In aspects, the invention provides the composition of any one or more ofaspects 1-116, wherein the composition comprises a preservationcomponent comprising one or more constituents which (1) prevents thedetectable or significant degradation (e.g., loss of more than about 1%,about 2%, about 3%, about 4%, or loss of more than about 5%) of thebimatoprost compound, the detectable or significant degradation (e.g.,loss of more than about 1%, about 2%, about 3%, about 4%, or loss ofmore than about 5%) of the timolol compound, or the detectable orsignificant degradation (e.g., loss of more than about 1%, about 2%,about 3%, about 4%, or loss of more than about 5%) of each of thebimatoprost compound and the timolol compound, (2) prevents detectableor significant microbial growth in the composition such that thecomposition becomes unsuitable (unsafe) for use, (3) prevents theaccumulation of a detectable or significant level of impurities suchthat the composition becomes unsuitable for use, e.g., would fail tomeet requirements for impurities established by a recognized regulatorybody such as the United States Food and Drug Administration, or (4) anycombination of (1)-(4) such that the composition remains suitable foruse when stored at about 25° C. +/−2° C. and about 65% relativehumidity, when stored at about 40° C. +/−2° C. and about 75% relativehumidity, or when stored under either condition, or a sequentialcombination of such conditions, for at least about 1 month, such as atleast about 3, 6, 9, or 12 months or more (aspect 117).

In aspects, the invention provides the composition of any one or more ofaspects 1-117, wherein the composition comprises a preservationcomponent comprising at least one constituent which provides detectableor significant preservation activity and detectable or significantpenetration enhancement of the bimatoprost compound, the timololcompound, or both the bimatoprost compound and the timolol compound(aspect 118).

In aspects, the invention provides the composition of any one or more ofaspects 1-118, wherein the composition comprises a preservationcomponent comprising one or more constituents which is not benzalkoniumchloride, in addition to benzalkonium chloride present in thecomposition (aspect 119).

In aspects, the invention provides the composition of any one or more ofaspects 1-120, wherein the only component of the preservation componentis the benzalkonium chloride described in any one or more of aspects41-43 (aspect 120).

In aspects, the invention provides the composition of any one or more ofaspects 1-120, wherein the composition comprises a chelation componentcomprising one or more constituents providing detectable or significantchelation activity (aspect 121).

In aspects, the invention provides the composition of any one or more ofaspects 1-121, wherein the composition does not comprise any constituentproviding detectable or significant chelation activity (aspect 122).

In aspects, the invention provides the composition of any one or more ofaspects 1-122, wherein the composition comprises a carrier component(aspect 123).

In aspects, the invention provides the composition of any one or more ofaspects 1-123, wherein the composition comprises a carrier component andwherein the carrier component is at least substantially comprised ofwater (aspect 124).

In aspects, the invention provides the composition of any one or more ofaspects 1-124, wherein the composition comprises water in an amountrepresenting at least about 50% w/v of the composition (aspect 125).

In aspects, the invention provides the composition of any one or more ofaspects 1-125, wherein the composition comprises water in an amountrepresenting at least about 75% w/v of the composition (aspect 126).

In aspects, the invention provides the composition of any one or more ofaspects 1-126, wherein the composition comprises water in an amountrepresenting at least about 90% w/v of the composition (aspect 127).

In aspects, the invention provides the composition of any one or more ofaspects 1-127, wherein the composition is characterizable as an aqueouscomposition (aspect 128).

In aspects, the invention provides the composition of any one or more ofaspects 1-128, wherein the composition comprises a pH adjustingcomponent comprising one or more constituents in sufficient amounts toestablish the pH of the composition at about 6.2-about 7.8, such as,e.g., about 6.2-about 7, or, e.g., or about 6.9-about 7.5 (aspect 129).

In aspects, the invention provides the composition of any one or more ofaspects 1-129, wherein the composition comprises a pH adjustingcomponent comprising one or both of sodium hydroxide and hydrochloricacid (aspect 130).

In aspects, the invention provides the composition of any one or more ofaspects 1-130, wherein the composition comprises a pH adjustingcomponent comprising one or both of sodium hydroxide and hydrochloricacid in an amount sufficient to establish the pH of the composition atabout 6.2-about 7.8, such as, e.g., about 6.2-about 7 or, e.g., about6.9-about 7.5 (aspect 131).

In aspects, the invention provides the composition of any one or more ofaspects 1-131, wherein the composition comprises a pH adjustingcomponent comprising hydrochloric acid in an amount sufficient toestablish the pH of the composition at about 6.2-about 7.8, such as,e.g., about 6.2-about 7 or, e.g., about 6.9-about 7.5 (aspect 132).

In aspects, the invention provides the composition of any one or more ofaspects 1-132, wherein the composition comprises a pH adjustingcomponent comprising sodium chloride and hydrochloric acid in an amountsufficient to establish the pH of the composition at about 6.2-about7.8, such as, e.g., about 6.2-about 7 or, e.g., about 6.9-about 7.5(aspect 133).

In aspects, the invention provides the composition of any one or more ofaspects 1-133, wherein the composition maintains a pH of about 6.2 toabout 7.8, such as, e.g., about 6.2-about 7, or, e.g., about 6.9-about7.5, when storage at about 15° C.-about 27° C. and about 60% relativehumidity, after storage at about 38° C.-about 42° C. and 75% relativehumidity, or after storage under either condition, or a sequentialcombination of such conditions, for at least about one month, such as1-3 months, 2-6 months, 5-9 months, 8-12 months, 10-18 months, 12-24months, 20-30 months, 28-36 months, or for more than 36 months (aspect134).

In aspects, the invention provides the composition of any one or more ofaspects 1-134, wherein the composition maintains a pH of about 6.2 toabout 7.8, such as, e.g., about 6.2-about 7 or, e.g., 6.9-about 7.5 whenstorage at about 15° C.-about 27° C. and about 60% relative humidity,after storage at about 38° C.-about 42° C. and 75% relative humidity, orafter storage under either condition, or a sequential combination ofsuch conditions, for at least about one month, such as 1-3 months, 2-6months, 5-9 months, 8-12 months, 10-18 months, 12-24 months, 20-30months, 28-36 months, or for more than 36 months (aspect 135).

In aspects, the invention provides the composition of any one or more ofaspects 1-135, wherein the composition maintains a pH of about 6.2-about7 when storage at about 15° C.-about 27° C. and about 60% relativehumidity, after storage at about 38° C.-about 42° C. and 75% relativehumidity, or after storage under either condition, or a sequentialcombination of such conditions, for at least about one month, such as1-3 months, 2-6 months, 5-9 months, 8-12 months, 10-18 months, 12-24months, 20-30 months, 28-36 months, or for more than 36 months (aspect136).

In aspects, the invention provides the composition of any one or more ofaspects 1-136, wherein the composition maintains a pH of about 6.9 toabout 7.5 or, e.g., about 7.1 to about 7.3 when storage at about 15°C.-about 27° C. and about 60% relative humidity, after storage at about38° C.-about 42° C. and 75% relative humidity, or after storage undereither condition, or a sequential combination of such conditions, for atleast about one month, such as 1-3 months, 2-6 months, 5-9 months, 8-12months, 10-18 months, 12-24 months, 20-30 months, 28-36 months, or formore than 36 months (aspect 137).

In aspects, the invention provides the composition of any one or more ofaspects 1-137, wherein the composition has a pH of about 6.2-about 7.8(aspect 138).

In aspects, the invention provides the composition of any one or more ofaspects 1-138, wherein the composition has a pH of about 6.2-about 7.5(aspect 139).

In aspects, the invention provides the composition of any one or more ofaspects 1-139, wherein the composition has a pH of about 6.2-about 7(aspect 140).

In aspects, the invention provides the composition of any one or more ofaspects 1-140, wherein the composition has a pH of about 6.9-about 7.5(aspect 141).

In aspects, the invention provides the composition of any one or more ofaspects 1-141, wherein the composition has a pH of about 7.0-about 7.4(aspect 142).

In aspects, the invention provides the composition of any one or more ofaspects 1-141, wherein the composition has a pH of about 7.1-about 7.3(aspect 143).

In aspects, the invention provides the composition of any one or more ofaspects 1-143, wherein the composition has an osmolality of betweenabout 270-about 370 mOsm/Kg (aspect 144).

In aspects, the invention provides the composition of any one or more ofaspects 1-144, wherein the composition has an osmolality of betweenabout 280-about 330 mOsm/Kg (aspect 145).

In aspects, the invention provides the composition of any one or more ofaspects 1-145, wherein the composition is suitable for use in methods oftreating one or more ocular conditions selected from the groupconsisting of glaucoma, elevated intraocular pressure, elevatedintraocular pressure associated with glaucoma (such as, e.g., associatedwith open-angle glaucoma), visual impairment associated with elevatedintraocular pressure, or any combination thereof (aspect 146).

In aspects, the invention provides the composition of any one or more ofaspects 1-146, wherein the composition is suitable for use in methods oftreating elevated intraocular pressure such as elevated intraocularpressure associated with glaucoma, e.g., open-angle glaucoma (aspect147).

In aspects, the invention provides the composition of any one or more ofaspects 1-147, wherein the composition is distributed into single-doseor multidose containers (aspect 148).

In aspects, the invention provides the composition of any one or more ofaspects 1-148, wherein the composition is distributed into single-dosecontainers (aspect 149).

In aspects, the invention provides the composition of any one or more ofaspects 1-148, wherein the composition is distributed into multidosecontainers (aspect 150).

In aspects, the invention provides the composition of any one or more ofaspects 1-150, wherein the composition maintains at least about 97% ofthe bimatoprost compound and at least 97% of the timolol compound whenstored at about 25° C. +/−2° C. and about 65% relative humidity, whenstored at about 40° C. +/−2° C. and about 75% relative humidity, or whenstored under either condition, or a sequential combination of suchconditions, for at least about one month, e.g., at least about 2 months,at least about 3 months, at least about 2-about 6 months, about 3-about9 months, about 6-about 12 months, about 9-about 18 months, about12-about 24 months, about 18-about 30 months, about 24-about 36 months,or, e.g., for at least about 36 months (aspect 151).

In aspects, the invention provides the composition of any one or more ofaspects 1-151, wherein the composition maintains at least about 98% ofthe bimatoprost compound and at least 97% of the timolol compound whenstored at about 25° C. +/−2° C. and about 65% relative humidity, whenstored at about 40° C. +/−2° C. and about 75% relative humidity, or whenstored under either condition, or a sequential combination of suchconditions, for at least about one month, e.g., at least about 2 months,at least about 3 months, at least about 2-about 6 months, about 3-about9 months, about 6-about 12 months, about 9-about 18 months, about12-about 24 months, about 18-about 30 months, about 24-about 36 months,or, e.g., for at least about 36 months (aspect 152).

In aspects, the invention provides the composition of any one or more ofaspects 1-152, wherein the composition maintains at least about 99% ofthe bimatoprost compound and at least 97% of the timolol compound whenstored at about 25° C. +/−2° C. and about 65% relative humidity, whenstored at about 40° C. +/−2° C. and about 75% relative humidity, or whenstored under either condition, or a sequential combination of suchconditions, for at least about one month, e.g., at least about 2 months,at least about 3 months, at least about 2-about 6 months, about 3-about9 months, about 6-about 12 months, about 9-about 18 months, about12-about 24 months, about 18-about 30 months, about 24-about 36 months,or, e.g., for at least about 36 months (aspect 153).

In aspects, the invention provides the composition of any one or more ofaspects 1-156, wherein the composition comprises less than about 2.5%total impurities after storage at about 15° C.-about 27° C. and about60% relative humidity, after storage at about 38° C.-about 42° C. and75% relative humidity, or after storage under either condition, f or asequential combination of such conditions, or a period of at least about1 month, e.g., at least about 2 months, at least about 3 months, atleast about 2-about 6 months, about 3-about 9 months, about 6-about 12months, about 9-about 18 months, about 12-about 24 months, about18-about 30 months, about 24-about 36 months, or, e.g., for at leastabout 36 months (aspect 154).

In one aspect, the invention provides a pharmaceutically acceptable andophthalmologically suitable composition for treating an ocular conditionin a mammalian eye comprising (1) about 0.005% w/v-about 0.02% w/v of abimatoprost compound; (2) about 0.4% w/v-about 0.8% w/v of a timololcompound; (3) about 0.003%-about 0.007% of a quaternary ammonium salt;(4) about 0.25% w/v-about 2.5% w/v of a penetration enhancer component;and (5) optionally one or more excipients, wherein the ratio of thequaternary ammonium salt to the penetration enhancer component isbetween about 1:35-about 1:840, and wherein the composition is stablewhen stored at about 25° C. +/−2° C. and about 65% relative humidity,when stored at about 40° C. +/−2° C. and about 75% relative humidity, orwhen stored under either condition, or a sequential combination of suchconditions, for at least about 1 month, e.g., at least about 2 months,at least about 3 months, at least about 2-about 6 months, about 3-about9 months, about 6-about 12 months, about 9-about 18 months, about12-about 24 months, about 18-about 30 months, about 24-about 36 months,or, e.g., for at least about 36 months (aspect 155).

In one aspect, the invention provides a pharmaceutically acceptable andophthalmologically suitable composition for treating an ocular conditionin a mammalian eye comprising (1) about 0.005% w/v-about 0.02% w/v of abimatoprost compound; (2) about 0.4% w/v-about 0.8% w/v of a timololcompound; (3) about 0.003%-about 0.007% of a quaternary ammonium salt;and (4) about 0.25% w/v-about 2.5% w/v of a penetration enhancercomponent, wherein the ratio of the bimatoprost compound to thepenetration enhancer component is about 1:12.5-about 1:500, wherein thecomposition is stable when stored at about 25° C. +/−2° C. and about 65%relative humidity, when stored at about 40° C. +/−2° C. and about 75%relative humidity, or when stored under either condition, or asequential combination of such conditions, for at least about 1 month,e.g., at least about 2 months, at least about 3 months, at least about2-about 6 months, about 3-about 9 months, about 6-about 12 months, about9-about 18 months, about 12-about 24 months, about 18-about 30 months,about 24-about 36 months, or, e.g., for at least about 36 months (aspect156).

In one aspect, the invention provides a pharmaceutically acceptable andophthalmologically suitable composition for treating an ocular conditionin a mammalian eye comprising (1) about 0.005% w/v-about 0.02% w/v of abimatoprost compound; (2) about 0.4% w/v-about 0.8% w/v of a timololcompound; (3) about 0.003%-about 0.007% of a quaternary ammonium salt;and (4) about 0.25% w/v-about 2.5% w/v of a penetration enhancercomponent, wherein the ratio of the timolol compound to the penetrationenhancer component is between about 3.2:1-1:6.3 (e.g., ˜3.2:1-˜1:6.25),wherein the composition is stable when stored at about 25° C. +/−2° C.and about 65% relative humidity, when stored at about 40° C. +/−2° C.and about 75% relative humidity, or when stored under either condition,or a sequential combination of such conditions, for at least about 1month, e.g., at least about 2 months, at least about 3 months, at leastabout 2-about 6 months, about 3-about 9 months, about 6-about 12 months,about 9-about 18 months, about 12-about 24 months, about 18-about 30months, about 24-about 36 months, or, e.g., for at least about 36 months(aspect 157).

In aspects, the invention provides the composition of any one or more ofaspects 155-157, wherein the composition further comprises any one ormore of the characteristics described in any one or more of aspects1-154 (aspect 158). 1-154, wherein the composition is provided in theform of a solution, suspension, ointment, gel, emulsion, oil, or otherdosage form suitable for topical administration to the mammalian eye(aspect 159).

In aspects, the invention provides the composition of any one or more ofaspects 1-159, wherein the composition is provided in the form of asolution (aspect 160).

In aspects, the invention provides the composition of any one or more ofaspects 1-159, wherein the composition is provided in the form of a gel(aspect 161).

In one aspect, the invention provides a pharmaceutically acceptable andophthalmologically suitable composition in the form of a solution fortreating an ocular condition in a mammalian eye comprising (1) about0.005% w/v-about 0.02% w/v of a bimatoprost compound; (2) about 0.4%w/v-about 0.8% w/v of a timolol compound; (3) about 0.003%-about 0.007%of a quaternary ammonium salt; and (4) about 0.25% w/v-about 2.5% w/v ofa penetration enhancer component, wherein the ratio of the quaternaryammonium salt to the penetration enhancer component is between about1:36-about 1:834 (aspect 162).

In one aspect, the invention provides a pharmaceutically acceptable andophthalmologically suitable composition in the form of a solution fortreating an ocular condition in a mammalian eye comprising (1) about0.005% w/v-about 0.02% w/v of a bimatoprost compound; (2) about 0.4%w/v-about 0.8% w/v of a timolol compound; (3) about 0.003%-about 0.007%of a quaternary ammonium salt; (4) about 0.25% w/v-about 2.5% w/v of apenetration enhancer component; and (5) optionally one or moreexcipients, wherein the ratio of the quaternary ammonium salt to thepenetration enhancer component is between about 1:36-about 1:834, andwherein the composition is stable when stored at about 25° C. +/−2° C.and about 65% relative humidity, when stored at about 40° C. +/−2° C.and about 75% relative humidity, or when stored under either condition,or a sequential combination of such conditions, for at least about 1month, e.g., at least about 2 months, at least about 3 months, at leastabout 2-about 6 months, about 3-about 9 months, about 6-about 12 months,about 9-about 18 months, about 12-about 24 months, about 18-about 30months, about 24-about 36 months, or, e.g., for at least about 36 months(aspect 163).

In one aspect, the invention provides a pharmaceutically acceptable andophthalmologically suitable composition in the form of a gel fortreating an ocular condition in a mammalian eye comprising (1) about0.005% w/v-about 0.02% w/v of a bimatoprost compound; (2) about 0.4%w/v-about 0.8% w/v of a timolol compound; (3) about 0.003%-about 0.007%of a quaternary ammonium salt; and (4) about 0.25% w/v-about 2.5% w/v ofa penetration enhancer component, wherein the ratio of the quaternaryammonium salt to the penetration enhancer component is between about1:36-about 1:834 (aspect 164).

In one aspect, the invention provides a pharmaceutically acceptable andophthalmologically suitable composition in the form of a gel fortreating an ocular condition in a mammalian eye comprising (1) about0.005% w/v-about 0.02% w/v of a bimatoprost compound; (2) about 0.4%w/v-about 0.8% w/v of a timolol compound; (3) about 0.003%-about 0.007%of a quaternary ammonium salt; (4) about 0.25% w/v-about 2.5% w/v of apenetration enhancer component; and (5) optionally one or moreexcipients, wherein the ratio of the quaternary ammonium salt to thepenetration enhancer component is between about 1:25-about 1:2500, andwherein the composition is stable when stored at about 25° C. +/−2° C.and about 65% relative humidity, when stored at about 40° C. +/−2° C.and about 75% relative humidity, or when stored under either condition,or a sequential combination of such conditions, for at least about 1month, e.g., at least about 2 months, at least about 3 months, at leastabout 2-about 6 months, about 3-about 9 months, about 6-about 12 months,about 9-about 18 months, about 12-about 24 months, about 18-about 30months, about 24-about 36 months, or, e.g., for at least about 36 months(aspect 165).

In aspects, the invention provides the compositions of any one or bothof aspects 164-165, wherein the ratio of bimatoprost compound, e.g.,bimatoprost base, to the viscosity enhancer component is about 1:2 toabout 1:1000 (aspect 166).

In aspects, the invention provides the composition of aspect 166,wherein the ratio of bimatoprost compound, e.g., bimatoprost base, tothe viscosity enhancer component is about 1:1 to about 1:500 (aspect167).

In aspects, the invention provides the compositions of aspect 167,wherein the ratio of bimatoprost compound, e.g., bimatoprost base, tothe viscosity enhancer component is about 1:1 to about 1:100 (aspect168).

In aspects, the invention provides the composition of aspect 168,wherein the ratio of bimatoprost compound, e.g., bimatoprost base, tothe viscosity enhancer component is about 1:60 (aspect 169).

In aspects, the invention provides any one or more of the compositionsof aspects 164-169, wherein the ratio of timolol compound, e.g., a saltof timolol, e.g., timolol maleate, to the viscosity enhancer componentis about 10:1 to about 1:10 (aspect 170).

In aspects, the invention provides the composition of aspect 170,wherein the ratio of timolol compound, e.g., a salt of timolol, e.g.,timolol maleate, to the viscosity enhancer component is about 5:1 toabout 1:5 (aspect 171).

In aspects, the invention provides the composition of aspect 171,wherein the ratio of timolol compound, e.g., a salt of timolol, e.g.,timolol maleate, to the viscosity enhancer component is about 2:1 toabout 1:2 (aspect 172).

In aspects, the invention provides the composition of aspect 172,wherein the ratio of timolol compound, e.g., a salt of timolol, e.g.,timolol maleate, to the viscosity enhancer component is about 1.13:1(aspect 173).

In aspects, the invention provides the composition of any one or more ofaspects 164-173, wherein the composition comprises a viscosity enhancercomponent and wherein the ratio of the total amount of API consisting ofthe bimatoprost compound, e.g., bimatoprost base, and the timololcompound, e.g., salt of timolol, e.g., timolol maleate, to the viscosityenhancer component is about 10.5:1 to about 1:9.9 (aspect 174).

In aspects, the invention provides the composition of aspect 174,wherein the ratio of the total amount of API consisting of thebimatoprost compound, e.g., bimatoprost base, and the timolol compound,e.g., salt of timolol, e.g., timolol maleate, to the viscosity enhancercomponent is about 5:1 to about 1:5 (aspect 175).

In aspects, the invention provides the composition of aspect 175,wherein the ratio of the total amount of API consisting of thebimatoprost compound, e.g., bimatoprost base, and the timolol compound,e.g., salt of timolol, e.g., timolol maleate, to the viscosity enhancercomponent is about 3:1 to about 1:2 (aspect 176).

In aspects, the invention provides the composition of aspect 176,wherein the ratio of the total amount of API consisting of thebimatoprost compound, e.g., bimatoprost base, and the timolol compound,e.g., salt of timolol, e.g., timolol maleate, to the viscosity enhancercomponent is about 1:1.15 (aspect 177).

In aspects, the invention provides the composition of any one or more ofaspects 164-177, wherein the composition further comprises any one ormore of the characteristics described in any one or more of aspects1-154 (aspect 178).

In one aspect, the invention provides a pharmaceutically acceptable andophthalmologically suitable gel composition for treating an ocularcondition in a mammalian eye comprising (1) about 0.005% w/v-about 0.02%w/v of a bimatoprost compound; (2) about 0.4% w/v-about 0.8% w/v of atimolol compound; (3) about 0.003%-about 0.007% of a quaternary ammoniumsalt, and (4) about 0.1% w/v-about 1% w/v of a viscosity enhancingcomponent, wherein the viscosity of the composition detectably orsignificantly increases (a) upon exposure to the environment of themammalian eye to which it is administered, (b) upon exposure totemperatures of at least about 32 degrees Celsius (° C.), (c) uponexposure to an environment having an ionic strength detectably orsignificantly greater than that of one or more gelling agents present inthe composition (e.g., gellan gum), (d) exposure to an environmenthaving a pH of greater than about 6.2, or (e) any combination of(a)-(d), over the viscosity of the composition while stored prior toadministration at a temperature of between about 15° C. to about 25° C.+/−2° C.) (aspect 179).

In one aspect, the invention provides a pharmaceutically acceptable andophthalmologically suitable gel composition for treating an ocularcondition in a mammalian eye comprising (1) about 0.005% w/v-about 0.02%w/v of a bimatoprost compound; (2) about 0.4% w/v-about 0.8% w/v of atimolol compound; and (3) about 0.003%-about 0.007% of a quaternaryammonium salt, wherein the viscosity of the composition detectably orsignificantly increases (a) upon exposure to the environment of themammalian eye to which it is administered, (b) upon exposure totemperatures of at least about 32 degrees Celsius (° C.), (d) uponexposure to an environment having an ionic strength detectably orsignificantly greater than that of one or more gelling agents present inthe composition (e.g., gellan gum), (d) exposure to an environmenthaving a pH of greater than about 6.2, or (e) any combination of(a)-(d), over the viscosity of the composition while stored prior toadministration at a temperature of between about 15° C. to about 25° C.+/−2° C.), wherein the composition is stable when stored at about 25° C.+/−2° C. and about 65% relative humidity, when stored at about 40° C.+/−2° C. and about 75% relative humidity, or when stored under eithercondition, or a sequential combination of such conditions (aspect 180).

In one aspect, the invention provides the composition of aspect 180,wherein the composition further comprises about 0.1% w/v-about 1% w/v ofa viscosity enhancing component (aspect 181).

In one aspect, the invention provides a pharmaceutically acceptable andophthalmologically suitable gel composition for treating an ocularcondition in a mammalian eye comprising (1) about 0.005% w/v-about 0.02%w/v of a bimatoprost compound, and (2) about 0.4% w/v-about 0.8% w/v ofa timolol compound (aspect 182).

In one aspect, the invention provides a pharmaceutically acceptable andophthalmologically suitable gel composition for treating an ocularcondition in a mammalian eye comprising (1) about 0.005% w/v-about 0.02%w/v of a bimatoprost compound, and (2) about 0.4% w/v-about 0.8% w/v ofa timolol compound, wherein (a) upon exposure to the environment of themammalian eye to which it is administered, (b) upon exposure totemperatures of at least about 32 degrees Celsius (° C.), (d) uponexposure to an environment having an ionic strength detectably orsignificantly greater than that of one or more gelling agents present inthe composition (e.g., gellan gum), (d) exposure to an environmenthaving a pH of greater than about 6.2, or (e) any combination of(a)-(d), over the viscosity of the composition while stored prior toadministration at a temperature of between about 15° C. to about 25° C.+/−2° C.), wherein the composition is stable when stored at about 25° C.+/−2° C. and about 65% relative humidity, when stored at about 40° C.+/−2° C. and about 75% relative humidity, or when stored under eithercondition, or a sequential combination of such conditions (aspect 183).

In aspects, the invention provides the composition of any one or both ofaspect 182 or aspect 183, wherein the composition further comprises apreservative component (aspect 184).

In aspects, the invention provides the composition of aspect 184,wherein the preservative component comprises one or more quaternaryammonium salts (aspect 185).

In aspects, the invention provides the composition of aspect 185,wherein the preservative component is at least substantially comprisedof benzalkonium chloride (aspect 186).

In aspects, the invention provides the composition of aspect 186,wherein the composition comprises benzalkonium chloride in an amountrepresenting about 0.003% w/v-about 0.007% w/v of the composition(aspect 187).

In aspects, the invention provides the composition of any one or more ofaspects 182-187, wherein the composition comprises a penetrationenhancer component (aspect 188).

In aspects, the invention provides the composition of aspect 188,wherein the penetration enhancer component is present in the compositionin an amount of between about 0.25% w/v-about 2.5% w/v of thecomposition (aspect 189).

In aspects, the invention provides the composition of aspect 189,wherein the penetration component is at least substantially comprised ofone or more compounds selected from a group consisting of polyethylenesorbitan fatty acid esters, tocopherol polyethylene glycol succinate(TPGS), and polyoxyl hydrogenated castor oil (aspect 190).

In aspects, the invention provides the composition of aspect 190,wherein the penetration enhancer component is at least substantiallycomprised of a polyethylene sorbitan fatty acid ester selected from thegroup consisting of polyoxyethylene sorbitan laurate (polysorbate 20),polyoxyethylene sorbitan palmitate (polysorbate 40), a polyoxyethylenesorbitan stearate (polysorbate 60), a polyoxyethylene sorbitan tristearate (polysorbate 65), or a polyoxyethylene sorbitanoleate/polyoxyethylene sorbitan mono-oleate ester (e.g., polysorbate80), or a combination thereof (aspect 191).

In aspects, the invention provides the composition of aspect 191,wherein the penetration enhancer component is at least substantiallycomprised of polysorbate 20, polysorbate 80, or a combination ofpolysorbate 20 and polysorbate 80 (aspect 192).

In aspects, the invention provides the composition of aspect 192,wherein the penetration enhancer component is at least substantiallycomprised of polysorbate 80 (aspect 193).

In aspects, the invention provides the composition of aspect 190,wherein the penetration enhancer component is at least substantiallycomprised of TPGS (aspect 194).

In aspects, the invention provides the composition of aspect 190,wherein the penetration enhancer component is at least substantiallycomprised of a constituent characterizable as a polyoxyl hydrogenatedcastor oil (aspect 195).

In aspects, the invention provides the composition of aspect 195,wherein the penetration enhancer component is at least substantiallycomprised of polyoxyl 35 castor oil (cremophor EL) (aspect 196).

In aspects, the invention provides the composition of any one or more ofaspects 188-196, wherein the composition comprises both a preservativecomponent comprising a quaternary ammonium salt (e.g., benzalkoniumchloride) and a penetration enhancer component, wherein the ratio of thequaternary ammonium salt (e.g., benzalkonium chloride) to thepenetration enhancer component is about 1: about 35 to about 1: about840 (aspect 197).

In aspects, the invention provides the composition of aspect 197,wherein the ratio of the quaternary ammonium salt (e.g., benzalkoniumchloride) to the penetration enhancer component is about 1: about 100 toabout 1: about 300 (aspect 198).

In aspects, the invention provides the composition of aspect 198,wherein the ratio of the quaternary ammonium salt (e.g., benzalkoniumchloride) to the penetration enhancer component is about 1: about 200(aspect 199).

In aspects, the invention provides the composition of any one or more ofaspects 179-199, wherein the composition further comprises at least oneconstituent characterizable as a solubilizer, e.g., tromethamine (aspect200).

In aspects, the invention provides the composition of aspect 200,wherein the composition comprises a penetration enhancer component andwherein the penetration enhancer component comprises at least oneconstituent which detectably or significantly increases thesolubilization of one or more active pharmaceutical ingredients in thecomposition (e.g., bimatoprost compound, timolol compound, or both),such that the composition comprises at least two solubilizationconstituents which each provide detectable or significant solubilizationeffect (e.g., each detectably or significantly increase thesolubilization of one or more active pharmaceutical ingredients such asbimatoprost compound, timolol compound, or both) (aspect 201).

In aspects, the invention provides the compositions of any one or moreof aspects 179-201, wherein the ratio of bimatoprost compound, e.g.,bimatoprost base, to the viscosity enhancer component, when present inthe composition, is about 1:2 to about 1:1000 (aspect 202).

In aspects, the invention provides the composition of aspect 202,wherein the ratio of bimatoprost compound, e.g., bimatoprost base, tothe viscosity enhancer component, when present in the composition, isabout 1:1 to about 1:500 (aspect 203).

In aspects, the invention provides the compositions of aspect 203,wherein the ratio of bimatoprost compound, e.g., bimatoprost base, tothe viscosity enhancer component, when present in the composition, isabout 1:1 to about 1:100 (aspect 204).

In aspects, the invention provides the composition of aspect 204,wherein the ratio of bimatoprost compound, e.g., bimatoprost base, tothe viscosity enhancer component is about 1:60 (aspect 205).

In aspects, the invention provides any one or more of the compositionsof aspects 179-205, wherein the ratio of timolol compound, e.g., a saltof timolol, e.g., timolol maleate, to the viscosity enhancer component,when present in the composition, is about 10:1 to about 1:10 (aspect206).

In aspects, the invention provides the composition of aspect 206,wherein the ratio of timolol compound, e.g., a salt of timolol, e.g.,timolol maleate, to the viscosity enhancer component is about 5:1 toabout 1:5 (aspect 207).

In aspects, the invention provides the composition of aspect 207,wherein the ratio of timolol compound, e.g., a salt of timolol, e.g.,timolol maleate, to the viscosity enhancer component is about 2:1 toabout 1:2 (aspect 208).

In aspects, the invention provides the composition of aspect 208,wherein the ratio of timolol compound, e.g., a salt of timolol, e.g.,timolol maleate, to the viscosity enhancer component is about 1.13:1(aspect 209).

In aspects, the invention provides any one or more of the compositionsof aspects 179-209, wherein the ratio of the total amount of APIconsisting of the bimatoprost compound, e.g., bimatoprost base, and thetimolol compound, e.g., salt of timolol, e.g., timolol maleate, to theviscosity enhancer component is about 10.5:1 to about 1:9.9, such as,e.g., about 5:1 to about 1:5 or about 3:1 to about 1:2, e.g., about1:1.15 (aspect 210).

In aspects, the invention provides the composition of any one or more ofaspects 179-210, wherein the composition further comprises any one ormore of the characteristics described in any one or more of aspects1-154 (aspect 211).

In aspects, the invention provides the composition of any one or more ofaspects 182-211, wherein the composition comprises about 0.1% w/v-about1% w/v of a viscosity enhancing component (aspect 212).

In aspects, the invention provides a method of treating elevatedintraocular pressure, glaucoma, or both, in a mammalian eye, the methodcomprising administration of an effective amount of a compositioncomprising (1) about 0.005% w/v-about 0.02% w/v of a bimatoprostcompound; (2) about 0.4% w/v-about 0.8% w/v of a timolol compound; (3)about 0.003%-about 0.007% of a quaternary ammonium salt; and (4) about0.25% w/v-about 2.5% w/v of a penetration enhancer component, wherein(1) the ratio of the quaternary ammonium salt to the penetrationenhancer component is between about 1:35-about 1:840; (2) the ratio ofthe bimatoprost compound to the penetration enhancer component is about1:12.5-about 1:500; (3) the ratio of the timolol compound to thepenetration enhancer component is between about 3.2:1-1:6.3 (e.g.,˜3.2:1-˜1:6.25); or (4) any combination of (1), (2), and (3) are true(aspect 213).

In aspects, the invention provides a method of treating elevatedintraocular pressure, glaucoma, or both, in a mammalian eye, the methodcomprising administration of an effective amount of a compositionprovided in the form of a solution comprising (1) about 0.005% w/v-about0.02% w/v of a bimatoprost compound; (2) about 0.4% w/v-about 0.8% w/vof a timolol compound; (3) about 0.003%-about 0.007% of a quaternaryammonium salt; and (4) about 0.25% w/v-about 2.5% w/v of a penetrationenhancer component, wherein (1) the ratio of the quaternary ammoniumsalt to the penetration enhancer component is between about 1:36-about1:834; (2) the ratio of the bimatoprost compound to the penetrationenhancer component is about 1:12.5-about 1:500; (3) the ratio of thetimolol compound to the penetration enhancer component is between about3.2:1-1:6.3 (e.g., ˜3.2:1-˜1:6.25); or (4) any combination of (1), (2),and (3) are true (aspect 214).

In aspects, the invention provides a method of treating elevatedintraocular pressure, glaucoma, or both, in a mammalian eye, the methodcomprising administration of an effective amount of a gel compositioncomprising (1) about 0.005% w/v-about 0.02% w/v of a bimatoprostcompound; (2) about 0.4% w/v-about 0.8% w/v of a timolol compound; (3)about 0.003%-about 0.007% of a quaternary ammonium salt; and (4) about0.25% w/v-about 2.5% w/v of a penetration enhancer component, wherein(1) the ratio of the quaternary ammonium salt to the penetrationenhancer component is between about 1:36-about 1:834; (2) the ratio ofthe bimatoprost compound to the penetration enhancer component is about1:12.5-about 1:500; (3) the ratio of the timolol compound to thepenetration enhancer component is between about 3.2:1-1:6.3 (e.g.,˜3.2:1-˜1:6.25); or (4) any combination of (1), (2), and (3) are true(aspect 215).

In aspects, the invention provides a method of treating elevatedintraocular pressure, glaucoma, or both, in a mammalian eye, the methodcomprising administration of an effective amount of a gel compositioncomprising (1) about 0.005% w/v-about 0.02% w/v of a bimatoprostcompound; (2) about 0.4% w/v-about 0.8% w/v of a timolol compound; (3)about 0.003%-about 0.007% of a quaternary ammonium salt, and (4) whereinthe viscosity of the composition detectably or significantly increases(1) upon exposure to the environment of the mammalian eye to which it isadministered, (2) upon exposure to temperatures of at least about 32degrees Celsius (° C.), (3) upon exposure to an environment having anionic strength detectably or significantly greater than that of one ormore gelling agents present in the composition (e.g., gellan gum), (4)exposure to an environment having a pH of greater than about 6.2, or (5)any combination of (1)-(4), over the viscosity of the composition whilestored prior to administration at a temperature of between about 15° C.to about 25° C. +/−2° C.), wherein the composition is stable when storedat about 25° C. +/−2° C. and about 65% relative humidity, when stored atabout 40° C. +/−2° C. and about 75% relative humidity, or when storedunder either condition, or a sequential combination of such conditions,for at least one month (aspect 216).

In aspects, the invention provides the method of any one or more ofaspects 213-216, wherein the method is clinically demonstrated to be aseffective or detectably or significantly more effective than treatmentof the same or at least essentially the same, generally the same, or thesame condition with about the same amount of a reference compositionconsisting of 0.3 mg/mL (0.03% w/v) bimatoprost, 6.8 mg/mL (0.68% w/v)timolol maleate (an amount equivalent to 5 mg/mL or 0.5% w/v timolol),0.05 mg (0.005% w/v) benzalkonium chloride, sodium chloride, sodiumphosphate dibasic heptahydrate, citric acid monohydrate, hydrochloricacid and/or sodium hydroxide, and water for the same or similarindication (e.g., reducing IOP) and for at least substantially the sameadministration period as determined by one or more well-controlled andadequate clinical studies performed in compliance with generallyprevailing regulatory authority standards (aspect 217).

In aspects, the invention provides the method of any one or more ofaspects 213-217, wherein the method is clinically demonstrated to be aseffective or detectably or significantly more effective than treatmentof the same or at least essentially the same, generally the same, or thesame condition with about the same amount of the product approved asEuropean Medicines Agency product number EMEA/H/C/000668 for the same orsimilar indication (e.g., reducing IOP) and for at least substantiallythe same administration period (aspect 218).

In aspects, the invention provides the method of any one or more ofaspects 213-218, wherein the method is clinically demonstrated to be aseffective or detectably or significantly more effective than treatmentof the same or at least essentially the same, generally the same, or thesame condition with about the same amount of a reference compositionconsisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timolol maleate in anamount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v)benzalkonium chloride; optionally one or more of sodium chloride, sodiumphosphate dibasic heptahydrate, citric acid monohydrate, hydrochloricacid and/or sodium hydroxide; and water for the same or similarindication (e.g., reducing IOP) and for at least substantially the sameadministration period (aspect 219).

In aspects, the invention provides the method of any one or more ofaspects 1-219, wherein performance of the method results in asignificantly lower level of any one or more of the adverse eventsreported in section 4.8 (“Undesirable Effects”) of the productinformation sheet for the product approved as European Medicines Agencyproduct number EMEA/H/C/000668 (GANFORT®), having first received marketapproval on May 19, 2006, first published on May 3, 2010, and availableon the Web at:ema.europa.eu/en/documents/product-information/ganfort-epar-product-information_en.pdf(aspect 220).

In aspects, the invention provides the method of any one or more ofaspects 213-220, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of ocular redness compared to treatment of the same orat least essentially the same, generally the same, or the same conditionwith about the same amount of (1) the product approved as EuropeanMedicines Agency product number EMEA/H/C/000668; (2) a referencecomposition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost, 6.8 mg/mL(0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mL or 0.5% w/vtimolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodium chloride,sodium phosphate dibasic heptahydrate, citric acid monohydrate,hydrochloric acid and/or sodium hydroxide; (3) a reference compositionconsisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timolol maleate in anamount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v)benzalkonium chloride; optionally one or more of sodium chloride, sodiumphosphate dibasic heptahydrate, citric acid monohydrate, hydrochloricacid and/or sodium hydroxide; and water; or (4) any combination thereof,for at least substantially the same administration period (aspect 221).

In aspects, the invention provides the method of any one or more ofaspects 213-221, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of ocular burning compared to treatment of the same orat least essentially the same, generally the same, or the same conditionwith about the same amount of (1) the product approved as EuropeanMedicines Agency product number EMEA/H/C/000668; (2) a referencecomposition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost, 6.8 mg/mL(0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mL or 0.5% w/vtimolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodium chloride,sodium phosphate dibasic heptahydrate, citric acid monohydrate,hydrochloric acid and/or sodium hydroxide; (3) a reference compositionconsisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timolol maleate in anamount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v)benzalkonium chloride; optionally one or more of sodium chloride, sodiumphosphate dibasic heptahydrate, citric acid monohydrate, hydrochloricacid and/or sodium hydroxide; and water; or (4) any combination thereof,for at least substantially the same administration period (aspect 222).

In aspects, the invention provides the method of any one or more ofaspects 213-222, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of ocular itching compared to treatment of the same orat least essentially the same, generally the same, or the same conditionwith about the same amount of (1) the product approved as EuropeanMedicines Agency product number EMEA/H/C/000668; (2) a referencecomposition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost, 6.8 mg/mL(0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mL or 0.5% w/vtimolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodium chloride,sodium phosphate dibasic heptahydrate, citric acid monohydrate,hydrochloric acid and/or sodium hydroxide; (3) a reference compositionconsisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timolol maleate in anamount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v)benzalkonium chloride; optionally one or more of sodium chloride, sodiumphosphate dibasic heptahydrate, citric acid monohydrate, hydrochloricacid and/or sodium hydroxide; and water; or (4) any combination thereof,for at least substantially the same administration period (aspect 223).

In aspects, the invention provides the method of any one or more ofaspects 213-223, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of ocular stinging compared to treatment of the sameor at least essentially the same, generally the same, or the samecondition with about the same amount of (1) the product approved asEuropean Medicines Agency product number EMEA/H/C/000668; (2) areference composition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost,6.8 mg/mL (0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mLor 0.5% w/v timolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; (3) a referencecomposition consisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timololmaleate in an amount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL(0.01% w/v) benzalkonium chloride; optionally one or more of sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; and water; or(4) any combination thereof, for at least substantially the sameadministration period (aspect 224).

In aspects, the invention provides the method of any one or more ofaspects 213-224, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of conjunctival irritation (irritation of theconjunctiva) compared to treatment of the same or at least essentiallythe same, generally the same, or the same condition with about the sameamount of (1) the product approved as European Medicines Agency productnumber EMEA/H/C/000668; (2) a reference composition consisting of 0.3mg/mL (0.03% w/v) bimatoprost, 6.8 mg/mL (0.68% w/v) timolol maleate (anamount equivalent to 5 mg/mL or 0.5% w/v timolol), 0.05 mg (0.005% w/v)benzalkonium chloride, sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; (3) a reference composition consisting of 0.1 mg/mL (0.01%w/v) bimatoprost; timolol maleate in an amount equivalent to 5 mg/mL(0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v) benzalkonium chloride;optionally one or more of sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; and water; or (4) any combination thereof, for at leastsubstantially the same administration period (aspect 225).

In aspects, the invention provides the method of any one or more ofaspects 213-225, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of sensitivity to light compared to treatment of thesame or at least essentially the same, generally the same, or the samecondition with about the same amount of (1) the product approved asEuropean Medicines Agency product number EMEA/H/C/000668; (2) areference composition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost,6.8 mg/mL (0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mLor 0.5% w/v timolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; (3) a referencecomposition consisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timololmaleate in an amount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL(0.01% w/v) benzalkonium chloride; optionally one or more of sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; and water; or(4) any combination thereof, for at least substantially the sameadministration period (aspect 226).

In aspects, the invention provides the method of any one or more ofaspects 213-226, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of eye pain compared to treatment of the same or atleast essentially the same, generally the same, or the same conditionwith about the same amount of (1) the product approved as EuropeanMedicines Agency product number EMEA/H/C/000668; (2) a referencecomposition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost, 6.8 mg/mL(0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mL or 0.5% w/vtimolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodium chloride,sodium phosphate dibasic heptahydrate, citric acid monohydrate,hydrochloric acid and/or sodium hydroxide; (3) a reference compositionconsisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timolol maleate in anamount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v)benzalkonium chloride; optionally one or more of sodium chloride, sodiumphosphate dibasic heptahydrate, citric acid monohydrate, hydrochloricacid and/or sodium hydroxide; and water; or (4) any combination thereof,for at least substantially the same administration period (aspect 227).

In aspects, the invention provides the method of any one or more ofaspects 213-227, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of sticky eye(s) compared to treatment of the same orat least essentially the same, generally the same, or the same conditionwith about the same amount of (1) the product approved as EuropeanMedicines Agency product number EMEA/H/C/000668; (2) a referencecomposition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost, 6.8 mg/mL(0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mL or 0.5% w/vtimolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodium chloride,sodium phosphate dibasic heptahydrate, citric acid monohydrate,hydrochloric acid and/or sodium hydroxide; (3) a reference compositionconsisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timolol maleate in anamount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v)benzalkonium chloride; optionally one or more of sodium chloride, sodiumphosphate dibasic heptahydrate, citric acid monohydrate, hydrochloricacid and/or sodium hydroxide; and water; or (4) any combination thereof,for at least substantially the same administration period (aspect 228).

In aspects, the invention provides the method of any one or more ofaspects 213-228, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of dry eye(s) compared to treatment of the same or atleast essentially the same, generally the same, or the same conditionwith about the same amount of (1) the product approved as EuropeanMedicines Agency product number EMEA/H/C/000668; (2) a referencecomposition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost, 6.8 mg/mL(0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mL or 0.5% w/vtimolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodium chloride,sodium phosphate dibasic heptahydrate, citric acid monohydrate,hydrochloric acid and/or sodium hydroxide; (3) a reference compositionconsisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timolol maleate in anamount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v)benzalkonium chloride; optionally one or more of sodium chloride, sodiumphosphate dibasic heptahydrate, citric acid monohydrate, hydrochloricacid and/or sodium hydroxide; and water; or (4) any combination thereof,for at least substantially the same administration period (aspect 229).

In aspects, the invention provides the method of any one or more ofaspects 213-229, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of the sensation that something is in the recipient'seye(s) compared to treatment of the same or at least essentially thesame, generally the same, or the same condition with about the sameamount of (1) the product approved as European Medicines Agency productnumber EMEA/H/C/000668; (2) a reference composition consisting of 0.3mg/mL (0.03% w/v) bimatoprost, 6.8 mg/mL (0.68% w/v) timolol maleate (anamount equivalent to 5 mg/mL or 0.5% w/v timolol), 0.05 mg (0.005% w/v)benzalkonium chloride, sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; (3) a reference composition consisting of 0.1 mg/mL (0.01%w/v) bimatoprost; timolol maleate in an amount equivalent to 5 mg/mL(0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v) benzalkonium chloride;optionally one or more of sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; and water; or (4) any combination thereof, for at leastsubstantially the same administration period (aspect 230).

In aspects, the invention provides the method of any one or more ofaspects 213-230, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of detectable or significant breaks in the surface ofthe eye either with or without associated inflammation compared totreatment of the same or at least essentially the same, generally thesame, or the same condition with about the same amount of (1) theproduct approved as European Medicines Agency product numberEMEA/H/C/000668; (2) a reference composition consisting of 0.3 mg/mL(0.03% w/v) bimatoprost, 6.8 mg/mL (0.68% w/v) timolol maleate (anamount equivalent to 5 mg/mL or 0.5% w/v timolol), 0.05 mg (0.005% w/v)benzalkonium chloride, sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; (3) a reference composition consisting of 0.1 mg/mL (0.01%w/v) bimatoprost; timolol maleate in an amount equivalent to 5 mg/mL(0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v) benzalkonium chloride;optionally one or more of sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; and water; or (4) any combination thereof, for at leastsubstantially the same administration period (aspect 231).

In aspects, the invention provides the method of any one or more ofaspects 213-231, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of detectable or significant reduction in clear visioncompared to treatment of the same or at least essentially the same,generally the same, or the same condition with about the same amount of(1) the product approved as European Medicines Agency product numberEMEA/H/C/000668; (2) a reference composition consisting of 0.3 mg/mL(0.03% w/v) bimatoprost, 6.8 mg/mL (0.68% w/v) timolol maleate (anamount equivalent to 5 mg/mL or 0.5% w/v timolol), 0.05 mg (0.005% w/v)benzalkonium chloride, sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; (3) a reference composition consisting of 0.1 mg/mL (0.01%w/v) bimatoprost; timolol maleate in an amount equivalent to 5 mg/mL(0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v) benzalkonium chloride;optionally one or more of sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; and water; or (4) any combination thereof, for at leastsubstantially the same administration period (aspect 232).

In aspects, the invention provides the method of any one or more ofaspects 213-232, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of redness and itching of the eyelid(s) compared totreatment of the same or at least essentially the same, generally thesame, or the same condition with about the same amount of (1) theproduct approved as European Medicines Agency product numberEMEA/H/C/000668; (2) a reference composition consisting of 0.3 mg/mL(0.03% w/v) bimatoprost, 6.8 mg/mL (0.68% w/v) timolol maleate (anamount equivalent to 5 mg/mL or 0.5% w/v timolol), 0.05 mg (0.005% w/v)benzalkonium chloride, sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; (3) a reference composition consisting of 0.1 mg/mL (0.01%w/v) bimatoprost; timolol maleate in an amount equivalent to 5 mg/mL(0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v) benzalkonium chloride;optionally one or more of sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; and water; or (4) any combination thereof, for at leastsubstantially the same administration period (aspect 233).

In aspects, the invention provides the method of any one or more ofaspects 213-233, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of hair growth around treated eye(s) compared totreatment of the same or at least essentially the same, generally thesame, or the same condition with about the same amount of (1) theproduct approved as European Medicines Agency product numberEMEA/H/C/000668; (2) a reference composition consisting of 0.3 mg/mL(0.03% w/v) bimatoprost, 6.8 mg/mL (0.68% w/v) timolol maleate (anamount equivalent to 5 mg/mL or 0.5% w/v timolol), 0.05 mg (0.005% w/v)benzalkonium chloride, sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; (3) a reference composition consisting of 0.1 mg/mL (0.01%w/v) bimatoprost; timolol maleate in an amount equivalent to 5 mg/mL(0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v) benzalkonium chloride;optionally one or more of sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; and water; or (4) any combination thereof, for at leastsubstantially the same administration period (aspect 234).

In aspects, the invention provides the method of any one or more ofaspects 213-234, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of darkening of the eyelid(s) compared to treatment ofthe same or at least essentially the same, generally the same, or thesame condition with about the same amount of (1) the product approved asEuropean Medicines Agency product number EMEA/H/C/000668; (2) areference composition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost,6.8 mg/mL (0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mLor 0.5% w/v timolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; (3) a referencecomposition consisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timololmaleate in an amount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL(0.01% w/v) benzalkonium chloride; optionally one or more of sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; and water; or(4) any combination thereof, for at least substantially the sameadministration period (aspect 235).

In aspects, the invention provides the method of any one or more ofaspects 213-235, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of darkening of the skin color around the treatedeye(s) compared to treatment of the same or at least essentially thesame, generally the same, or the same condition with about the sameamount of (1) the product approved as European Medicines Agency productnumber EMEA/H/C/000668; (2) a reference composition consisting of 0.3mg/mL (0.03% w/v) bimatoprost, 6.8 mg/mL (0.68% w/v) timolol maleate (anamount equivalent to 5 mg/mL or 0.5% w/v timolol), 0.05 mg (0.005% w/v)benzalkonium chloride, sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; (3) a reference composition consisting of 0.1 mg/mL (0.01%w/v) bimatoprost; timolol maleate in an amount equivalent to 5 mg/mL(0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v) benzalkonium chloride;optionally one or more of sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; and water; or (4) any combination thereof, for at leastsubstantially the same administration period (aspect 236).

In aspects, the invention provides the method of any one or more ofaspects 213-236, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of eyelash lengthening compared to treatment of thesame or at least essentially the same, generally the same, or the samecondition with about the same amount of (1) the product approved asEuropean Medicines Agency product number EMEA/H/C/000668; (2) areference composition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost,6.8 mg/mL (0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mLor 0.5% w/v timolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; (3) a referencecomposition consisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timololmaleate in an amount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL(0.01% w/v) benzalkonium chloride; optionally one or more of sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; and water; or(4) any combination thereof, for at least substantially the sameadministration period (aspect 237).

In aspects, the invention provides the method of any one or more ofaspects 213-237, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of ocular irritation compared to treatment of the sameor at least essentially the same, generally the same, or the samecondition with about the same amount of (1) the product approved asEuropean Medicines Agency product number EMEA/H/C/000668; (2) areference composition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost,6.8 mg/mL (0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mLor 0.5% w/v timolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; (3) a referencecomposition consisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timololmaleate in an amount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL(0.01% w/v) benzalkonium chloride; optionally one or more of sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; and water; or(4) any combination thereof, for at least substantially the sameadministration period (aspect 238).

In aspects, the invention provides the method of any one or more ofaspects 213-238, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of eye watering compared to treatment of the same orat least essentially the same, generally the same, or the same conditionwith about the same amount of (1) the product approved as EuropeanMedicines Agency product number EMEA/H/C/000668; (2) a referencecomposition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost, 6.8 mg/mL(0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mL or 0.5% w/vtimolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodium chloride,sodium phosphate dibasic heptahydrate, citric acid monohydrate,hydrochloric acid and/or sodium hydroxide; (3) a reference compositionconsisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timolol maleate in anamount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v)benzalkonium chloride; optionally one or more of sodium chloride, sodiumphosphate dibasic heptahydrate, citric acid monohydrate, hydrochloricacid and/or sodium hydroxide; and water; or (4) any combination thereof,for at least substantially the same administration period (aspect 239).

In aspects, the invention provides the method of any one or more ofaspects 213-239, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of swollen eyelid(s) compared to treatment of the sameor at least essentially the same, generally the same, or the samecondition with about the same amount of (1) the product approved asEuropean Medicines Agency product number EMEA/H/C/000668; (2) areference composition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost,6.8 mg/mL (0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mLor 0.5% w/v timolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; (3) a referencecomposition consisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timololmaleate in an amount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL(0.01% w/v) benzalkonium chloride; optionally one or more of sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; and water; or(4) any combination thereof, for at least substantially the sameadministration period (aspect 240).

In aspects, the invention provides the method of any one or more ofaspects 213-240, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of reduced vision compared to treatment of the same orat least essentially the same, generally the same, or the same conditionwith about the same amount of (1) the product approved as EuropeanMedicines Agency product number EMEA/H/C/000668; (2) a referencecomposition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost, 6.8 mg/mL(0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mL or 0.5% w/vtimolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodium chloride,sodium phosphate dibasic heptahydrate, citric acid monohydrate,hydrochloric acid and/or sodium hydroxide; (3) a reference compositionconsisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timolol maleate in anamount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v)benzalkonium chloride; optionally one or more of sodium chloride, sodiumphosphate dibasic heptahydrate, citric acid monohydrate, hydrochloricacid and/or sodium hydroxide; and water; or (4) any combination thereof,for at least substantially the same administration period (aspect 241).

In aspects, the invention provides the method of any one or more ofaspects 213-241, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of runny nose compared to treatment of the same or atleast essentially the same, generally the same, or the same conditionwith about the same amount of (1) the product approved as EuropeanMedicines Agency product number EMEA/H/C/000668; (2) a referencecomposition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost, 6.8 mg/mL(0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mL or 0.5% w/vtimolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodium chloride,sodium phosphate dibasic heptahydrate, citric acid monohydrate,hydrochloric acid and/or sodium hydroxide; (3) a reference compositionconsisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timolol maleate in anamount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v)benzalkonium chloride; optionally one or more of sodium chloride, sodiumphosphate dibasic heptahydrate, citric acid monohydrate, hydrochloricacid and/or sodium hydroxide; and water; or (4) any combination thereof,for at least substantially the same administration period (aspect 242).

In aspects, the invention provides the method of any one or more ofaspects 213-242, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of headache compared to treatment of the same or atleast essentially the same, generally the same, or the same conditionwith about the same amount of (1) the product approved as EuropeanMedicines Agency product number EMEA/H/C/000668; (2) a referencecomposition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost, 6.8 mg/mL(0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mL or 0.5% w/vtimolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodium chloride,sodium phosphate dibasic heptahydrate, citric acid monohydrate,hydrochloric acid and/or sodium hydroxide; (3) a reference compositionconsisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timolol maleate in anamount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v)benzalkonium chloride; optionally one or more of sodium chloride, sodiumphosphate dibasic heptahydrate, citric acid monohydrate, hydrochloricacid and/or sodium hydroxide; and water; or (4) any combination thereof,for at least substantially the same administration period (aspect 243).

In aspects, the invention provides the method of any one or more ofaspects 213-243, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of abnormal sensation(s) in the eye(s) compared totreatment of the same or at least essentially the same, generally thesame, or the same condition with about the same amount of (1) theproduct approved as European Medicines Agency product numberEMEA/H/C/000668; (2) a reference composition consisting of 0.3 mg/mL(0.03% w/v) bimatoprost, 6.8 mg/mL (0.68% w/v) timolol maleate (anamount equivalent to 5 mg/mL or 0.5% w/v timolol), 0.05 mg (0.005% w/v)benzalkonium chloride, sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; (3) a composition reference consisting of 0.1 mg/mL (0.01%w/v) bimatoprost; timolol maleate in an amount equivalent to 5 mg/mL(0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v) benzalkonium chloride;optionally one or more of sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; and water; or (4) any combination thereof, for at leastsubstantially the same administration period (aspect 244).

In aspects, the invention provides the method of any one or more ofaspects 213-244, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of iris inflammation compared to treatment of the sameor at least essentially the same, generally the same, or the samecondition with about the same amount of (1) the product approved asEuropean Medicines Agency product number EMEA/H/C/000668; (2) areference composition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost,6.8 mg/mL (0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mLor 0.5% w/v timolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; (3) a referencecomposition consisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timololmaleate in an amount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL(0.01% w/v) benzalkonium chloride; optionally one or more of sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; and water; or(4) any combination thereof, for at least substantially the sameadministration period (aspect 245).

In aspects, the invention provides the method of any one or more ofaspects 213-245, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of swollen conjunctiva compared to treatment of thesame or at least essentially the same, generally the same, or the samecondition with about the same amount of (1) the product approved asEuropean Medicines Agency product number EMEA/H/C/000668; (2) areference composition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost,6.8 mg/mL (0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mLor 0.5% w/v timolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; (3) a referencecomposition consisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timololmaleate in an amount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL(0.01% w/v) benzalkonium chloride; optionally one or more of sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; and water; or(4) any combination thereof, for at least substantially the sameadministration period (aspect 246).

In aspects, the invention provides the method of any one or more ofaspects 213-246, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of painful eyelid(s) compared to treatment of the sameor at least essentially the same, generally the same, or the samecondition with about the same amount of (1) the product approved asEuropean Medicines Agency product number EMEA/H/C/000668; (2) areference composition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost,6.8 mg/mL (0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mLor 0.5% w/v timolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; (3) a referencecomposition consisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timololmaleate in an amount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL(0.01% w/v) benzalkonium chloride; optionally one or more of sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; and water; or(4) any combination thereof, for at least substantially the sameadministration period (aspect 247).

In aspects, the invention provides the method of any one or more ofaspects 213-247, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of tired eye(s) compared to treatment of the same orat least essentially the same, generally the same, or the same conditionwith about the same amount of (1) the product approved as EuropeanMedicines Agency product number EMEA/H/C/000668; (2) a referencecomposition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost, 6.8 mg/mL(0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mL or 0.5% w/vtimolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodium chloride,sodium phosphate dibasic heptahydrate, citric acid monohydrate,hydrochloric acid and/or sodium hydroxide; (3) a reference compositionconsisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timolol maleate in anamount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v)benzalkonium chloride; optionally one or more of sodium chloride, sodiumphosphate dibasic heptahydrate, citric acid monohydrate, hydrochloricacid and/or sodium hydroxide; and water; or (4) any combination thereof,for at least substantially the same administration period (aspect 248).

In aspects, the invention provides the method of any one or more ofaspects 213-248, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of ingrown (in-growing) eyelash(es) compared totreatment of the same or at least essentially the same, generally thesame, or the same condition with about the same amount of (1) theproduct approved as European Medicines Agency product numberEMEA/H/C/000668; (2) a reference composition consisting of 0.3 mg/mL(0.03% w/v) bimatoprost, 6.8 mg/mL (0.68% w/v) timolol maleate (anamount equivalent to 5 mg/mL or 0.5% w/v timolol), 0.05 mg (0.005% w/v)benzalkonium chloride, sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; (3) a reference composition consisting of 0.1 mg/mL (0.01%w/v) bimatoprost; timolol maleate in an amount equivalent to 5 mg/mL(0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v) benzalkonium chloride;optionally one or more of sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; and water; or (4) any combination thereof, for at leastsubstantially the same administration period (aspect 249).

In aspects, the invention provides the method of any one or more ofaspects 213-249, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of darkening iris color compared to treatment of thesame or at least essentially the same, generally the same, or the samecondition with about the same amount of (1) the product approved asEuropean Medicines Agency product number EMEA/H/C/000668; (2) areference composition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost,6.8 mg/mL (0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mLor 0.5% w/v timolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; (3) a referencecomposition consisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timololmaleate in an amount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL(0.01% w/v) benzalkonium chloride; optionally one or more of sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; and water; or(4) any combination thereof, for at least substantially the sameadministration period (aspect 250).

In aspects, the invention provides the method of any one or more ofaspects 213-251, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of sunken eye appearance compared to treatment of thesame or at least essentially the same, generally the same, or the samecondition with about the same amount of (1) the product approved asEuropean Medicines Agency product number EMEA/H/C/000668; (2) areference composition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost,6.8 mg/mL (0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mLor 0.5% w/v timolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; (3) a referencecomposition consisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timololmaleate in an amount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL(0.01% w/v) benzalkonium chloride; optionally one or more of sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; and water; or(4) any combination thereof, for at least substantially the sameadministration period (aspect 251).

In aspects, the invention provides the method of any one or more ofaspects 213-251, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of separation of the eyelid from the surface of theeye compared to treatment of the same or at least essentially the same,generally the same, or the same condition with about the same amount of(1) the product approved as European Medicines Agency product numberEMEA/H/C/000668; (2) a reference composition consisting of 0.3 mg/mL(0.03% w/v) bimatoprost, 6.8 mg/mL (0.68% w/v) timolol maleate (anamount equivalent to 5 mg/mL or 0.5% w/v timolol), 0.05 mg (0.005% w/v)benzalkonium chloride, sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; (3) a reference composition consisting of 0.1 mg/mL (0.01%w/v) bimatoprost; timolol maleate in an amount equivalent to 5 mg/mL(0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v) benzalkonium chloride;optionally one or more of sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; and water; or (4) any combination thereof, for at leastsubstantially the same administration period (aspect 252).

In aspects, the invention provides the method of any one or more ofaspects 213-252, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of eyelash darkening compared to treatment of the sameor at least essentially the same, generally the same, or the samecondition with about the same amount of (1) the product approved asEuropean Medicines Agency product number EMEA/H/C/000668; (2) areference composition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost,6.8 mg/mL (0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mLor 0.5% w/v timolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; (3) a referencecomposition consisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timololmaleate in an amount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL(0.01% w/v) benzalkonium chloride; optionally one or more of sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; and water; or(4) any combination thereof, for at least substantially the sameadministration period (aspect 253).

In aspects, the invention provides the method of any one or more ofaspects 213-253, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of shortness of breath compared to treatment of thesame or at least essentially the same, generally the same, or the samecondition with about the same amount of (1) the product approved asEuropean Medicines Agency product number EMEA/H/C/000668; (2) areference composition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost,6.8 mg/mL (0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mLor 0.5% w/v timolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; (3) a referencecomposition consisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timololmaleate in an amount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL(0.01% w/v) benzalkonium chloride; optionally one or more of sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; and water; or(4) any combination thereof, for at least substantially the sameadministration period (aspect 254).

In aspects, the invention provides the method of any one or more ofaspects 213-254, wherein the effective amount is 1-2 drops of thecomposition administered once or twice daily over an effective treatmentperiod, and wherein the method results in detectably or significantlyreduced frequency of one or more of conjunctival hyperemia, tear filminstability, loss of goblet cells, conjunctival squamous metaplasia andapoptosis, disruption of the corneal epithelium barrier, damage to deepocular tissue, cystoid macular oedema (retinal swelling leading toworsening vision), eye swelling, blurred vision, ocular discomfort,difficulty breathing/wheezing, symptoms of allergic reaction (swelling,redness of the eye and rash of the skin) or hypersensitivity, changes intaste sensation, dizziness, slowing of heart rate, high blood pressure,difficulty sleeping, nightmare, asthma, hair loss, periocular skindiscoloration, and tiredness, or detectably or significantly reducedabsorption of BKC by soft contact lenses, compared to treatment of thesame or at least essentially the same, generally the same, or the samecondition with about the same amount of (1) the product approved asEuropean Medicines Agency product number EMEA/H/C/000668; (2) areference composition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost,6.8 mg/mL (0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mLor 0.5% w/v timolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; (3) a referencecomposition consisting of 0.1 mg/mL (0.01% w/v) bimatoprost; timololmaleate in an amount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL(0.01% w/v) benzalkonium chloride; optionally one or more of sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; and water; or(4) any combination thereof, for at least substantially the sameadministration period (aspect 255).

In aspects, the invention provides the method of any one or more ofaspects 213-255, wherein the method comprising the administration of areference composition consisting of both the bimatoprost compound andthe timolol compound is capable of reducing elevated intraocularpressure in a recipient suffering therefrom but who was previouslydemonstrated as being insufficiently responsive to a topicalbeta-blocker administered alone, a prostaglandin analogue administeredalone, or both (aspect 256).

In aspects, the invention provides the method of any one or more ofaspects 213-256, wherein the effective amount is 1-2 drops of thecomposition administered to a mammalian eye once or twice daily over aneffective treatment period, and the method is optionally repeated for anumber of times demonstrated to provide a significant clinical effect ina significant number of patients in a well-controlled and adequate studyor that is shown to be bioequivalent to a product that has beendemonstrated to achieve the at least substantially the same, generallythe same, or effectively the same clinical effect (aspect 257).

In aspects, the invention provides the method of any one or more ofaspects 213-257, wherein the effective amount is 1 drop of thecomposition administered to a mammalian eye once or twice daily over aneffective treatment period, and the method is optionally repeated for anumber of times demonstrated to provide a significant clinical effect ina significant number of patients in a well-controlled and adequate studyor that is shown to be bioequivalent to a product that has beendemonstrated to achieve the at least substantially the same, generallythe same, or effectively the same clinical effect (aspect 258).

In aspects, the invention provides the method of any one or more ofaspects 213-258, wherein the effective amount is 1 drop of thecomposition administered to a mammalian eye once daily over an effectivetreatment period, and the method is optionally repeated for a number oftimes demonstrated to provide a significant clinical effect in asignificant number of patients in a well-controlled and adequate studyor that is shown to be bioequivalent to a product that has beendemonstrated to achieve the at least substantially the same, generallythe same, or effectively the same clinical effect (aspect 259).

In aspects, the invention provides the method of any one or more ofaspects 213-259, wherein the method comprises the administration of thecomposition to each affected eye, both eyes, or only the dominant eye ofthe recipient over the course of an effective treatment period (aspect260).

In aspects, the invention provides the method of any one or more ofaspects 213-260, wherein the method comprises the administration of 1-2drops of the composition to each affected eye, both eyes, or thedominant eye of the recipient once or twice daily over the course of aneffective treatment period (aspect 261).

In aspects, the invention provides the method of any one or more ofaspects 213-261, wherein the method comprises the administration of 1drop of the composition to each affected eye, both eyes, or the dominanteye of the recipient once or twice daily over the course of an effectivetreatment period (aspect 262).

In aspects, the invention provides the method of any one or more ofaspects 213-262, wherein the method comprises the administration of 1drop of the composition to each affected eye, both eyes, or the dominanteye of the recipient once daily over the course of an effectivetreatment period (aspect 263).

In aspects, the invention provides the method of any one or more ofaspects 260-263, wherein the effective treatment period is a period oftime lasting between about 1 day and about 5 years (aspect 264).

In aspects, the invention provides the method of any one or more ofaspects 260-264, wherein the effective treatment period is a period oftime lasting between about 1 day and about 3 years (aspect 265).

In aspects, the invention provides the method of any one or more ofaspects 260-265, wherein the effective treatment period is a period oftime lasting between about 1 day and about 1 year (aspect 266).

In aspects, the invention provides the method of any one or more ofaspects 260-266, wherein the effective treatment period is a period oftime lasting between about 1 day and about 6 months (aspect 267).

In aspects, the invention provides the method of any one or more ofaspects 260-267, wherein the effective treatment period is a period oftime lasting between about 1 day and about 3 months (aspect 268).

In aspects, the invention provides the method of any one or more ofaspects 260-268, wherein the effective treatment period is a period oftime lasting between about 1 day and about 1 month (aspect 269).

In aspects, the invention provides the method of any one or more ofaspects 260-269, wherein the effective treatment period is a period oftime lasting between about 1 day and about 5 days (aspect 270).

In aspects, the invention provides the method of any one or more ofaspects 260-270, wherein the effective treatment period is a period oftime lasting between about 1 day and about 1 week (aspect 271).

In aspects, the invention provides the method of any one or more ofaspects 260-271, wherein the effective treatment period is a period oftime lasting between about 5 days and about 1 month (aspect 272).

In aspects, the invention provides the method of any one or more ofaspects 260-272, wherein the effective treatment period is a period oftime lasting between about 2 weeks and about 3 months (aspect 273).

In aspects, the invention provides the method of any one or more ofaspects 260-273, wherein the effective treatment period is a period oftime lasting between about 1 month and about 6 months (aspect 274).

In aspects, the invention provides the method of any one or more ofaspects 260-274, wherein the effective treatment period is a period oftime lasting between about 3 months and about 9 months (aspect 275).

In aspects, the invention provides the method of any one or more ofaspects 260-275, wherein the effective treatment period is a period oftime lasting between about 6 months and about 12 months (aspect 276).

In aspects, the invention provides the method of any one or more ofaspects 260-276, wherein the effective treatment period is a period oftime lasting between about 9 months and about 18 months (aspect 277).

In aspects, the invention provides the method of any one or more ofaspects 260-277, wherein the effective treatment period is a period oftime lasting between about 12 months and about 24 months (aspect 278).

In aspects, the invention provides the method of any one or more ofaspects 260-278, wherein the effective treatment period is a period oftime lasting between about 18 months and about 30 months (aspect 279).

In aspects, the invention provides the method of any one or more ofaspects 260-279, wherein the effective treatment period is a period oftime lasting between about 24 months and about 36 months (aspect 280).

In aspects, the invention provides the method of any one or more ofaspects 260-280, wherein the method comprises chronic treatment, whereinthe effective treatment period is a period of time lasting more thanabout 3 years (aspect 281).

In aspects, the invention provides the method of any one or more ofaspects 260-281, wherein the method comprises chronic treatment, whereinthe effective treatment period is a period of time lasting more thanabout 5 years (aspect 282).

In aspects, the invention provides the method of any one or more ofaspects 213-281, wherein the method results in the user maintaining alonger course of therapy than the course of therapy tolerated by use of(1) the product approved as European Medicines Agency product numberEMEA/H/C/000668; (2) a reference composition consisting of 0.3 mg/mL(0.03% w/v) bimatoprost, 6.8 mg/mL (0.68% w/v) timolol maleate (anamount equivalent to 5 mg/mL or 0.5% w/v timolol), 0.05 mg (0.005% w/v)benzalkonium chloride, sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; (3) a reference composition consisting of 0.1 mg/mL (0.01%w/v) bimatoprost, 6.8 mg/mL (0.68% w/v) timolol maleate (an amountequivalent to 5 mg/mL or 0.5% w/v timolol), 0.05 mg (0.001% w/v)benzalkonium chloride, sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; (4) an ophthalmic composition demonstrating essentially thesame, generally the same, or the same intraocular pressure reductioncapability, (5) ophthalmic compositions comprising a higher amount ofbenzalkonium chloride, bimatoprost compound, timolol compound, or anycombination thereof, or (6) any combination thereof (aspect 283).

In aspects, the invention provides a method of manufacturing any one ormore of the compositions of any one or more of aspects 1-212, whereinthe method comprises (1) preparation of a bulk composition, (2) offlinefiltration of the bulk composition, (3) online filtration of the bulkcomposition, and (4) final packaging of the composition (aspect 284).

In aspects, the invention provides a method of manufacturing any one ormore of the compositions of any one or more of aspects 1-212, whereinthe method comprises (1) preparation of a bulk composition comprising(a) the preparation of a polymer phase solution; (b) the preparation ofa drug phase solution; and (c) filtration of the drug phase solutioninto the polymer phase solution; (2) filtration of the bulk composition;and (3) final packaging of the composition (aspect 285).

In aspects, the invention provides the method of manufacturing of anyone or both of aspect 284 or aspect 285, wherein the composition(s)resulting from the method are used in any one or more of the methods oftreatment in any one or more of aspects 213-283 (aspect 286).

In aspects, the invention provides a kit comprising a compositionaccording to any one or more of aspects 1-212, and a device suitable forfacilitating the delivery of the composition to a recipient eye (aspect287).

In aspects, the invention provides the kit of aspect 287, wherein thedevice is suitable for facilitating the delivery of the composition to arecipient eye is a container capable of delivering compositions heldtherein in a drop-by-drop manner (e.g., a dropper bottle) (aspect 288).

In aspects, the invention provides the kit any one or both of aspect 287or aspect 288, wherein the composition is provided within the deliverydevice/container (aspect 289).

In aspects, the invention provides the kit of any one or more of aspects287-289, wherein the kit comprises multiple doses of compositionprovided as a plurality of single-dose containers, a single multi-dosecontainer, or a plurality of multi-dose containers (aspect 290).

In aspects, the invention provides the kit of any one or more of aspects287-290, wherein the composition is a composition manufactured accordingto any one or more of the methods of manufacturing described in aspects284-286 (aspect 291).

In aspects, the invention provides the kit of any one or more of aspects287-291, wherein the kit is used in the method of treatment of any oneor more of aspects 213-283 (aspect 292).

In aspects, the invention provides a composition comprising at least onebimatoprost compound, at least one timolol compound, and at least onecompound capable of detectably or significantly enhancing thepenetration of the bimatoprost compound, the timolol compound, or boththe bimatoprost and the timolol compound into a tissue of the eye,wherein the composition has any one or more of the characteristicsdescribed in any one or more of aspects 1-212, wherein (1) thecomposition is utilized in any one or more of the methods of any one ormore of aspect 213-283, (2) the composition is manufactured according toa method described in any one or more of aspects 284-286, (3) thecomposition is present as a part of a kit according to any one or moreof 287-292, or (4) any combination of (1)-(3) (aspect 293).

In aspects, the invention provides a composition in the form of a gelcomprising at least one bimatoprost compound and at least one timololcompound wherein the composition has any one or more of thecharacteristics described in any one or more of aspects 1-212, wherein(1) the composition is utilized in any one or more of the methods of anyone or more of aspect 213-283, (2) the composition is manufacturedaccording to a method described in any one or more of aspects 284-286,(3) the composition is present as a part of a kit according to any oneor more of 287-292, or (4) any combination of (1)-(3) (aspect 294).

DETAILED DESCRIPTION OF THE INVENTION

For convenience, both combinations of elements/steps and individualelements/steps may be described in this section of this disclosure.Despite the inclusion of passages focused on specific elements/steps,any aspect, facet, embodiment, or other description of particularstep(s) or element(s) can be applied to any general description of thecompositions/methods of the invention, or any other recitedelement(s)/step(s) thereof, which are provided in any part of thisdisclosure.

As used herein, the word “exemplary” means “serving as an example,instance, or illustration.” The following detailed description is merelyexemplary in nature and is not intended to limit application and uses.Any embodiment described herein as “exemplary” is not necessarily to beconstrued as preferred or advantageous over other embodiments.

Compositions

In aspects, the invention provides pharmaceutically acceptable andophthalmologically suitable compositions comprising a prostaglandinanalogue component (PAC), comprising, e.g., a synthetic analogue ofprostaglandin F2a (PGF2a), and a beta-adrenoreceptor antagonist(“p-blocker”) component (BBC), and one or more excipients. In aspects,such compositions are suitable for ophthalmic administration, e.g., forthe treatment of one or more conditions of the eye, such as elevatedintraocular pressure (IOP), such as elevated IOP associated withglaucoma, e.g., open-angle glaucoma. In aspects, such compositions aresuitable for the treatment of impaired vision (improving vision orreducing impaired vision) associated with elevated IOP. In aspects, thePAC and the BBC represent the only active pharmaceutical ingredients(APIs) in the composition.

Prostaglandin Analogue Component (PAC)

In aspects, compositions provided by the invention comprise aprostaglandin analogue component (“PAC”) in addition to abeta-adrenoreceptor antagonist (β-blocker) component (BBC). In aspects,the PAC comprises one or more prostaglandin analogue compounds, e.g.,one or more synthetic analogue(s) of prostaglandin F2a. In aspects, theterm “prostaglandin analogue” used herein refers compounds which bind toa prostaglandin receptor, and which mimic the function of (e.g.,demonstrate at least essentially the same, at least generally the same,at least substantially the same, or the same biological function) asnaturally occurring prostaglandins. More specifically, in aspects, theterm “prostaglandin analogue” is used to describe a synthetic analogueof prostaglandin F2a (PGF2a).

In aspects, the PAC can comprise any pharmaceutically acceptable andophthalmologically suitable prostaglandin analogue agent/drug. Inaspects, examples of suitable PAC constituents include, e.g.,ophthalmologically suitable forms of latanoprost, travoprost,bimatoprost, tafluprost, latanoprostene bunod, alprostadil,dinoprostone, epoprostenol, treprostinil, iloprost, trimoprostil,rioprostil, cloprostenol, fluprostenol, luprostiol, etiproston,tiaprost, unoprostone and its derivatives such as, e.g., unoprostoneisopropyl, misoprostol, sulfoprostone, gemeprost, alfaprostol, anddelprostenate compound(s), etc. In certain aspects, the PAC comprisesone or more bimatoprost compound(s).

Bimatoprost Compounds

In aspects, the PAC of compositions provided by the invention comprisesone or more bimatoprost compounds (compounds that comprise bimatoprost,including derivatives thereof, or that include another compound that isa pharmaceutically acceptable analog of bimatoprost that exhibits atleast similar physiological/therapeutic effects as bimatoprost).

Analogs of bimatoprost may be suitable in compositions/methods of theinvention, such analogs being generated, e.g., by application of routinemethods. However, in aspects, certain compounds or groups of compoundsmay offer one or more different properties, such that each such compoundcan be considered its own aspect or to define a category of aspects ofthe invention. In aspects, the PAC does not include analogs ofbimatoprost, only bimatoprost, bimatoprost derivatives (a moleculecomprising a bimatoprost core and additional groups), or a relatedcompound (e.g., a salt of either or both thereof). In aspects, a PAConly comprises bimatoprost or a related compound, such as a saltthereof.

As disclosed above, bimatoprost ((Z)-7-[(1R, 2R, 3R, 5S)-3,5-Dihydroxy-2-[(1E,3S)˜3-hydroxy-5-phenyl˜1-pentenyl]cyclopentyl]˜5-N-ethylheptenamid) is asynthetic analogue of prostaglandin F2a (PGF2a) with a molecular weightof 415.58 g/mol and demonstrating ocular hypotensive activity, havingthe structure provided below.

In aspects, the bimatoprost compound can be any pharmaceuticallyacceptable and ophthalmologically suitable bimatoprost compound, suchas, e.g., any pharmaceutically acceptable and ophthalmologicallysuitable salt(s), pharmaceutically acceptable and ophthalmologicallysuitable solvate(s) (e.g., if identified/identifiable), pharmaceuticallyacceptable and ophthalmologically suitable hydrate(s), pharmaceuticallyacceptable and ophthalmologically suitable enantiomer(s),pharmaceutically acceptable and ophthalmologically suitablederivative(s), pharmaceutically acceptable and ophthalmologicallysuitable polymorph(s), and pharmaceutically acceptable andophthalmologically suitable prodrug(s) thereof. In aspects, abimatoprost compound is limited to one or some of these types ofcompound(s) but excludes other type(s) of any such compounds. E.g., inaspects, a bimatoprost compound does not include a polymorph, but doesinclude a salt of bimatoprost.

In aspects, exemplary salts of bimatoprost can include, e.g., thetromethamine salt of bimatoprost or bimatoprost salts disclosed in theart, such as, e.g., those disclosed in US20140316009A1 (Hughes).

In aspects, exemplary hydrates of bimatoprost can include, e.g., thosedisclosed in the art at the time of this filing, such as those disclosedin, e.g., CN104981450A (Wu).

In aspects, exemplary enantiomers of bimatoprost can include, e.g.,enantiomers of bimatoprost compounds (e.g., bimatoprost derivatives)disclosed in the art at the time of this filing, such as those disclosedin, e.g., WO2012112451, or disclosed by, e.g., Dams, et. al. in “A novelconvergent synthesis of the antiglaucoma PGF2a analogue bimatoprost,”Chirality. 2013 Mar.; 25(3):170-9.

In aspects, exemplary derivatives of bimatoprost can include, e.g.,bimatoprost derivatives disclosed in the art at the time of this filing,such as, e.g., those disclosed in WO2012112451 (Woodward) or, e.g.,WO2009136281A1 (Benedini).

In aspects, exemplary polymorphs of bimatoprost can include, e.g.,bimatoprost polymorphs disclosed in the art at the time of this filing,such as, e.g., those disclosed in, e.g., US2009163596 (Gutman) or, e.g.,U.S. Pat. No. 9,855,232 (Wu).

In aspects, the bimatoprost compound is not a prodrug. In alternativeaspects, a prodrug of bimatoprost or another bimatoprost compound isincorporated into a composition or used in a method. Prodrugs may beknown or developed where practical. Bimatoprost itself may or may notact as a prodrug. To the extent that bimatoprost acts as a prodrug orany other bimatoprost compound encompassed by this disclosure acts as aprodrug, readers will understand that any suitable metabolite of anysuch prodrug is simultaneously and implicitly provided by thisdisclosure and, uncontradicted, such metabolites are encompassed by thescope of bimatoprost compounds.

In aspects, compositions of the invention can comprise bimatoprost inany ophthalmologically acceptable form, such as for example bimatoprostin amorphous or crystalline forms (including polymorphic forms thereof);a pharmaceutically acceptable salt of bimatoprost (e.g., a tromethaminesalt thereof); or any mixtures thereof suitable for ophthalmic use.Accordingly, uncontradicted, the term “bimatoprost” or “bimatoprostcompound”, as used herein, can in aspects be interpreted as referring toany bimatoprost compound; that is, bimatoprost or any related compoundabove, e.g., one or more of its pharmaceutically acceptable salts,pharmaceutically acceptable solvates (if identified/identifiable),pharmaceutically acceptable hydrates, pharmaceutically acceptableenantiomers, pharmaceutically acceptable derivatives, pharmaceuticallyacceptable polymorphs and pharmaceutically acceptable prodrugs thereof.Uncontradicted, in aspects “bimatoprost” or “bimatoprost compound” canrefer to any metabolite, analog, or a derivative of bimatoprost capableof exhibiting functional and physical responses that are significantlysimilar to that of bimatoprost, e.g., such functional and physicalresponses similar to those of prostaglandins and/or metabolites, oranalogs or derivatives of bimatoprost exhibiting prostaglandin receptoractivity. Uncontradicted, in aspects “bimatoprost” or “bimatoprostcompound” refers to bimatoprost in hydrolyzed form. Uncontradicted, inaspects “bimatoprost” or “bimatoprost compound” refers to bimatoprost infree form or free acid form. In aspects, the bimatoprost of thecomposition is limited to only one, two, or some larger combination ofthe various types of bimatoprost compounds described herein or theirequivalents known in the art. In aspects, the bimatoprost component of acomposition is limited to one form of bimatoprost. In aspects, the PACcomprises bimatoprost base (bimatoprost base compound). In aspects, theonly constituent of the PAC is bimatoprost base.

Pac (Amount)

In aspects, the invention provides compositions comprising atherapeutically effective amount of a PAC comprising one or moreconstituents. In aspects, the effective amount is an amount capable ofinducing a statistically significant improvement in one or moreconditions, such as reducing IOP, treating glaucoma, etc. In aspects,compositions comprise an amount of a PAC capable of detectably orsignificantly lowering intraocular pressure (“IOP”), either alone or inconjunction with one or more additional active pharmaceuticalingredients (APIs) in recipient(s) (patient(s)) with ocular hypertension(e.g., as often experienced by glaucoma patients). In aspects,compositions comprise an amount of a PAC capable of detectably orsignificantly increasing outflow of aqueous humor through the trabecularmeshwork, uveoscleral, or both the trabecular meshwork and uveoscleralroutes.

In aspects, the PAC is present in compositions provided by the inventionin an amount representing about 0.001% w/v-about 0.05% w/v of thecomposition, such as, e.g., ˜0.001% w/v-˜0.045% w/v, ˜0.001% w/v-˜0.04%w/v, ˜0.001% w/v-˜0.035% w/v, ˜0.001% w/v-˜0.03% w/v, ˜0.001%w/v-˜0.025% w/v, ˜0.001% w/v-˜0.02% w/v, ˜0.001% w/v-˜0.015% w/v, or,e.g., ˜0.001% w/v-˜0.01% w/v of the composition. Note that herein, thephrase, “in an amount representing about” can be interpreted as such anamount provided “making up about” that amount (e.g., percentage, such as% w/v) of the composition; for example, disclosure of component orconstituent [X] present in an amount representing about [Y]% w/v of acomposition can be interpreted as component or constituent [X] making upabout [Y]% w/v of the composition.

In aspects, the PAC is present in compositions provided by the inventionin an amount representing ˜0.002% w/v-˜0.05% w/v, ˜0.004% w/v-˜0.05%w/v, ˜0.006% w/v-˜0.05% w/v, ˜0.008% w/v-˜0.05% w/v, or, e.g., ˜0.01%w/v-˜0.05% w/v of the composition.

In aspects, the PAC is present in compositions provided by the inventionin an amount representing ˜0.002% w/v-about 0.045% w/v of thecomposition, such as, e.g., ˜0.005% w/v-˜0.03% w/v, ˜0.005% w/v-˜0.025%w/v, ˜0.005% w/v-˜0.02% w/v, ˜0.007% w/v-˜0.02% w/v, ˜0.009% w/v-˜0.015%w/v, or, e.g., about 0.01% w/v of the composition.

In aspects, compositions provided herein comprise a PAC (e.g., such as,e.g., a bimatoprost compound, such as bimatoprost base) present in anamount representing no more than about 0.05% w/v, no more than about0.04% w/v, no more than about 0.03% w/v, no more than about 0.02% w/v,or no more than about 0.01% w/v of the composition(s).

In aspects, the PAC comprises two or more PAC constituents, wherein thetotal amount of such constituents is represented by theconcentrations/amounts provided above. In aspects, compositions comprisea PAC comprising a single PAC constituent, wherein the total amount ofsuch single constituent is represented by the concentrations/amountsprovided above. In aspects, the PAC comprises a pharmaceuticallyacceptable and ophthalmologically suitable bimatoprost compound, suchas, e.g., bimatoprost base. In aspects, the PAC comprises a singleconstituent which is a bimatoprost compound, e.g., bimatoprost base. Inaspects, the single bimatoprost compound constituent, e.g., bimatoprostbase, is present in compositions in the above-identified amounts. Inaspects, bimatoprost base is present in compositions in theabove-identified amounts.

In aspects, the PAC, e.g., in aspects the bimatoprost compound, ispresent in compositions provided by the invention in an amountrepresenting ˜0.001% w/v-˜0.01% w/v of the composition, ˜0.005%w/v-0.015% w/v of the composition, or e.g., ˜0.007% w/v-about 0.025% w/vof the composition. In aspects, advantages of such compositions caninclude, e.g., a reduction in the number or severity of one or more sideeffects known to be caused by bimatoprost compared to compositionscomprising a higher concentration of a bimatoprost compound, e.g.,compositions comprising greater than about 0.01% w/v, ≥˜0.02% w/v,≥˜0.03% w/v, ≥˜0.04% w/v, or, e.g., ≥˜0.05% w/v of a bimatoprostcompound.

In aspects, such amounts of a PAC, PAC constituents, or both, disclosedin this section represent an effective amount of a PAC, PAC constituent,or both.

Beta-Adrenoreceptor Antagonist (β-Blocker) Component (BBC)

In aspects, compositions provided by the invention comprise abeta-adrenoreceptor antagonist (β-blocker) (component (“BBC”) inaddition to a prostaglandin analogue component (PAC). In aspects, theBBC comprises one or more β-blocker compounds. In aspects, the term“β-blocker compound” used herein refers compounds which demonstratecompetitive antagonistic action on beta-adrenoreceptor (e.g.,beta-adrenoreceptors B1, B2, and B3).

In aspects, the BBC can comprise any pharmaceutically acceptable andophthalmologically suitable O-blocker compound. In aspects, examples ofsuitable PAC constituents include, e.g., timolol, betaxolol, carteolol,levobunolol, befunolol, metipranolol and mepindolol compound(s), etc. Incertain aspects, the BBC comprises one or more timolol compound(s).

Timolol Compounds

In aspects, the BBC of compositions provided by the invention comprisesone or more timolol compounds (compounds that comprise timolol,including derivatives thereof, or that include another compound that isa pharmaceutically acceptable analog of timolol that exhibits at leastsimilar physiological/therapeutic effects as timolol).

Analogs of timolol may be suitable in compositions/methods of theinvention, such analogs being generated, e.g., by application of routinemethods. However, in aspects, certain compounds or groups of compoundsmay offer one or more different properties, such that each such compoundcan be considered its own aspect or to define a category of aspects ofthe invention. In aspects, the BBC does not include analogs of timolol,only timolol, timolol derivatives (a molecule comprising a timolol coreand additional groups), or a related compound (e.g., a salt of either orboth thereof). In aspects, a BBC only comprises timolol or a relatedcompound, such as a salt thereof.

As disclosed above, timolol((-)-1-(tert-butylamino)˜3-[(4-morpholino-1,2,5-thiadiazol-3-yl)-oxy]-2-propanol)is a beta-adrenergic agent with a molecular weight of 316.421 g/mol andhaving the structure provided below.

In aspects, the timolol compound can be any pharmaceutically acceptableand ophthalmologically suitable timolol compound, such as, e.g., anypharmaceutically acceptable and ophthalmologically suitable salt(s),pharmaceutically acceptable and ophthalmologically suitable solvate(s),pharmaceutically acceptable and ophthalmologically suitable hydrate(s),pharmaceutically acceptable and ophthalmologically suitableenantiomer(s), pharmaceutically acceptable and ophthalmologicallysuitable derivative(s), pharmaceutically acceptable andophthalmologically suitable polymorph(s), and pharmaceuticallyacceptable and ophthalmologically suitable prodrug(s) thereof. Inaspects, a timolol compound is limited to one or some of these types ofcompound(s) but excludes other type(s) of any such compounds. E.g., inaspects, a timolol compound does not include a polymorph, but doesinclude a salt of timolol.

In aspects, compositions of the invention can comprise timolol in anyophthalmologically acceptable form, such as for example timolol in aderivatized form, a base form, or mixtures thereof suitable forophthalmic use. Accordingly, uncontradicted, the term “timolol” or“timolol compound”, as used herein, can in aspects be interpreted asreferring to any timolol compound; that is, timolol or any relatedcompound above, e.g., one or more of its pharmaceutically acceptablesalts, pharmaceutically acceptable solvates, pharmaceutically acceptablehydrates, pharmaceutically acceptable enantiomers, pharmaceuticallyacceptable derivatives, pharmaceutically acceptable polymorphs andpharmaceutically acceptable prodrugs thereof. Uncontradicted, in aspects“timolol” or “timolol compound” can refer to any metabolite, analog, ora derivative of timolol capable of exhibiting functional and physicalresponses that are significantly similar to that of timolol, e.g., suchfunctional and physical responses similar to those of β-blockers and/ormetabolites, or analogs or derivatives of timolol exhibitingbeta-adrenoreceptor antagonist activity. In aspects, the timolol of thecompositions is limited to only one, two, or some larger combination ofthe various types of timolol compounds described herein or theirequivalents known in the art. In aspects, the timolol component of acomposition is limited to one form of timolol. In aspects, the BBC ofthe compositions provided by the invention comprise a salt of timolol,such as, e.g., timolol maleate.

Timolol Maleate

Timolol maleate (the maleate salt form of timolol), is a non-selectivebeta-adrenergic receptor blocking agent, having the chemical name is(-)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol maleate (1:1) (salt). Timolol maleate is a white toalmost white, odorless powder with a molecular weight of 432.5 g/mol.

Bbc (Amount)

In aspects, the invention provides compositions comprising atherapeutically effective amount of a BBC comprising one or moreconstituents. In aspects, the effective amount is an amount capable ofinducing a statistically significant improvement in one or moreconditions, such as reducing IOP, treating glaucoma, etc. In aspects,compositions comprise an amount of a BBC capable of detectably orsignificantly lowering intraocular pressure (“IOP”), either alone or inconjunction with one or more additional active pharmaceuticalingredients (APIs) in recipient(s) (patient(s)) with ocular hypertension(e.g., as often experienced by glaucoma patients). In aspects,compositions comprise an amount of a BBC capable of detectably orsignificantly reducing the rate of aqueous humor formation throughreduction of flow to the ciliary process.

In aspects, the BBC is present in compositions provided by the inventionin an amount representing about 0.1% w/v-about 1% w/v of thecomposition, such as, e.g., ˜0.15% w/v-˜1% w/v, ˜0.2% w/v-˜1% w/v,˜0.25% w/v-˜1% w/v, ˜0.3% w/v-˜1% w/v, ˜0.35% w/v-˜1% w/v, ˜0.4% w/v-˜1%w/v, ˜0.45% w/v-˜1% w/v, or, e.g., ˜0.5% w/v-˜1% w/v of the composition.

In aspects, the BBC is present in compositions provided by the inventionin an amount representing ˜0.1% w/v-˜0.9% w/v, ˜0.1% w/v-˜0.8% w/v,˜0.1% w/v-˜0.7% w/v, ˜0.1% w/v-˜0.6% w/v, or, e.g., ˜0.1% w/v-˜0.5% w/vof the composition.

In aspects, the PAC is present in compositions provided by the inventionin an amount representing ˜0.15% w/v-about 0.9% w/v of the composition,such as, e.g., ˜0.2% w/v-˜0.85% w/v, ˜0.25% w/v-˜0.8% w/v, ˜0.3%w/v-˜0.75% w/v, ˜0.35% w/v-˜0.7% w/v, ˜0.4% w/v-˜0.7% w/v, ˜0.45%w/v-˜0.7% w/v, ˜0.5% w/v-˜0.7% w/v, ˜0.55% w/v-˜0.7% w/v, or, e.g.,about 0.5% w/v of the composition or, e.g., ˜0.68% w/v of thecomposition. In aspects, the PAC comprises a timolol compound, e.g., asalt of timolol, e.g., timolol maleate in an amount representing about0.68% of the composition. In aspects, 0.68% w/v timolol maleate (orabout 6.8 mg of timolol maleate) is equivalent to about 0.5% w/v timololfree base (or about 5 mg timolol free base). Such a conversion can beapplied elsewhere as applicable herein, as is routinely understood inthe art.

In aspects, the BBC comprises two or more BBC constituents, wherein thetotal amount of such constituents is represented by theconcentrations/amounts provided above. In aspects, compositions comprisea BBC comprising a single BBC constituent, wherein the total amount ofsuch single constituent is represented by the concentrations/amountsprovided above. In aspects, the BBC comprises a pharmaceuticallyacceptable and ophthalmologically suitable timolol compound, such as,e.g., a salt of timolol, e.g., timolol maleate. In aspects, the BBCcomprises a single constituent which is a timolol compound, e.g., a saltof timolol, e.g., timolol maleate. In aspects, the single timololcompound constituent, e.g., the salt of timolol, e.g., timolol maleate,is present in compositions in the above-identified amounts.

In aspects, the BBC, e.g., in aspects the timolol compound, e.g., saltof timolol, e.g., timolol maleate, is present in compositions providedby the invention in an amount representing ˜0.1% w/v-˜0.07% w/v of thecomposition, ˜0.4% w/v-0.8% w/v of the composition, or e.g., ˜0.5%w/v-about 1% w/v of the composition. In aspects, advantages of suchcompositions can include, e.g., a reduction in the number or severity ofone or more side effects known to be caused by timolol compared tocompositions comprising a higher concentration of a timolol compound,e.g., compositions comprising greater than about 0.7% w/v, ≥˜0.8% w/v,≥˜0.9% w/v, or, e.g., ≥˜1% w/v of timolol maleate. In aspects,advantages of such compositions can include, e.g., an increase in theefficacy of the timolol compound in providing a detectably orsignificant therapeutic effect, such as, a reduction in intraocularpressure, compared to compositions comprising a lower concentration of atimolol compound, e.g., compositions comprising less than about 0.5%w/v, ≤˜0.4% w/v, ≤˜0.3% w/v, ≤˜0.2% w/v, or ≤˜0.1% w/v of a timololcompound, or compared to compositions comprising a sub-therapeuticamount of a timolol compound.

In aspects, such amounts of a BBC, BBC constituents, or both, disclosedin this section represent an effective amount of a BBC, BBC constituent,or both.

Alternative or Additional Anti-Glaucoma Agent(s) Component (AGAC)

In certain aspects, compositions provided by the invention comprise aPAC comprising one or more constituents, e.g., a bimatoprost compound,and second component (the “alternative or additional anti-glaucomaagent(s) component” (“AGAC”)) comprising one or more antiglaucoma agentsnot characterizable as a beta-adrenoreceptor antagonist, such as, forexample, one or more pharmaceutically acceptable and ophthalmologicallysuitable carbonic anhydrase inhibitor(s), one or more pharmaceuticallyacceptable and ophthalmologically suitable alpha-adrenergic agonist(s),or both. In aspects, suitable carbonic anhydrase inhibitor(s) include,e.g., a brinzolamide compound, e.g., brinzolamide acetazolamide, amethazolamide compound, a dorzolamide compound, a diclofenamidecompound, an ethoxzolamide compound, a zonisamide compound, etc. Inaspects, suitable alpha-adrenergic agonist(s) include, e.g., abrimonidine compound, a clonidine compound, an apraclonidine compound, adexmedetomidine compound, a fadolmidine compound, etc.

In aspects, an AGAC can be present in compositions described herein asan alternative to the BBC or in addition to the BBC. In aspects, an AGACcan comprise one or more constituents and be present in compositionsdescribed herein in therapeutically effective amounts (e.g., in amountsproviding a detectable or therapeutic effect in treating glaucoma asdetermined by an appropriately conducted clinical trial).

Typically, an AGAC, combination of AGACs, or constituent(s) of one ormore AGACs, are individually or collectively present in an effectiveamount. In such context, an effective amount can be an amount thatdetectably or significantly enhances or modifies the therapeuticcapability/potential of the associated product or method. For example,an AGAC can detectably or significantly improve the treatment of one ormore conditions, e.g., glaucoma (such as open-angle glaucoma) or otherelevated intraocular pressure-related conditions.

In certain aspects, compositions do not comprise an AGAC component, andthe only APIs of the composition are present as a constituent of PAC orBBC.

Bimatoprost & Timolol Compound Combinations

In aspects, compositions provided by the invention comprise apharmaceutically acceptable and ophthalmologically suitable PAC (e.g., abimatoprost compound, such as, e.g., bimatoprost base) and apharmaceutically acceptable and ophthalmologically suitable BBC (e.g., atimolol compound, e.g., a salt of timolol, e.g., timolol maleate) incombination with one another (within a single composition). Suchcombination compositions can be referred to as “fixed dosage”combination products. Uncontradicted, the term “fixed dose” (AKA,“fixed-dose”) is understood in the art as referring to a combination oftwo or more active ingredients (API(s)) within a single form ofpharmaceutical administration and does not necessarily impart anylimitation on the relationship of dose(s) of such active ingredients,etc.). See, e.g., Goodman et al. Expert Review of Pharmacoeconomics &Outcomes Research, 20:1, 1-26. Nonetheless, in aspects, fixed-dosecombinations provided herein are characterized by specific amounts ofAPIs or relationships (e.g., ratios) of APIs, such ratio discussedelsewhere herein.

In one aspect, the pharmaceutically acceptable and ophthalmologicallysuitable compositions provided herein comprise both a bimatoprostcompound, e.g., bimatoprost base, and a timolol compound, e.g., a saltof timolol, e.g., timolol maleate, which are capable of detectably orsignificantly reducing elevated intraocular pressure in a recipient,e.g., adult patient(s), such as a recipient diagnosed with glaucoma(e.g., open-angle glaucoma) who are insufficiently responsive to topicalbeta-blockers alone or prostaglandin analogues alone.

In aspects, compositions provided by the invention comprise apharmaceutically acceptable and ophthalmologically suitable fixed-dosecombination of a PAC and a BBC. In aspects, the PAC and the BBCcomprise, e.g., a bimatoprost compound (e.g., bimatoprost base) and atimolol compound, respectively. In aspects, compositions provided by theinvention comprise, e.g., about 0.001% w/v-about 0.05% w/v of a PAC,e.g., ˜0.001% w/v-0.04% w/v, ˜0.001% w/v-0.03% w/v, ˜0.001% w/v-0.02%w/v, or ˜0.001% w/v-0.01% w/v (such as, in aspects, no more than about0.05% w/v, no more than about 0.04% w/v, no more than about 0.03% w/v,no more than about 0.02% w/v, or no more than about 0.01% w/v) of a PAC,such as, e.g., a bimatoprost compound, such as bimatoprost base. Inaspects, compositions provided by the invention further comprise, e.g.,about 0.1% w/v-about 1% w/v of a BBC, such as, e.g., ˜0.2% w/v-˜0.9%w/v, ˜0.3% w/v-˜0.8% w/v, ˜0.4% w/v-˜0.7% w/v, or, e.g., ˜0.5% w/v-˜0.7%w/v, such as, e.g., about 0.5% w/v or about 0.68% w/v of a BBC, such as,e.g., a timolol compound, such as a salt of timolol, e.g., timololmaleate.

In aspects, compositions provided by the invention comprise a totalamount of API (such as, e.g., a total amount of a bimatoprost compound,e.g., bimatoprost base, and timolol compound, e.g., a salt of timolol,e.g., timolol maleate) which represents about 0.1% w/v-about 1.5% w/v ofthe composition, such as, e.g., ˜0.1% w/v-˜1.2% w/v, ˜0.1% w/v-˜1% w/v,˜0.1% w/v-˜0.9% w/v, ˜0.1% w/v-˜0.8% w/v, or, e.g., ˜0.1% w/v-˜0.7% w/vof the composition.

In aspects, compositions provided by the invention comprise a totalamount of API (such as, e.g., a total amount of a bimatoprost compound,e.g., bimatoprost base, and timolol compound, e.g., a salt of timolol,e.g., timolol maleate) which represents about 0.1% w/v-about 1.5% w/v ofthe composition, such as, e.g., ˜0.2% w/v-˜1.5% w/v, ˜0.3% w/v-˜1.5%w/v, ˜0.4% w/v-˜1.5% w/v, ˜0.5% w/v-˜1.5% w/v, ˜0.6% w/v-˜1.5% w/v, or,e.g., ˜0.7% w/v-˜1.5% w/v of the composition.

In aspects, compositions provided by the invention comprise a totalamount of API (such as, e.g., a total amount of a bimatoprost compound,e.g., bimatoprost base, and timolol compound, e.g., a salt of timolol,e.g., timolol maleate) which represents about 0.2% w/v-about 1.2% w/v ofthe composition, such as, e.g., ˜0.2% w/v-˜1% w/v, ˜0.3% w/v-˜9% w/v,˜0.4% w/v-˜8% w/v, or, e.g., ˜0.5% w/v-˜0.7% w/v, such as for exampleabout 0.7% w/v or about 0.69% w/v of the composition.

In aspects, such amounts of total API disclosed in this sectionrepresent an effective amount of total API, e.g., an effective amount ofPAC and BBC, e.g., an effective amount of bimatoprost compound andtimolol compound.

Excipients

According to certain aspects, compositions provided by the inventioncomprise one or more excipients, which are a type of, or alternativelycan be characterized as, a composition constituent/component oringredient. In aspects, the one or more excipients can be anypharmaceutically acceptable and ophthalmologically acceptable excipientsprovided that the excipient(s) does/do not detectably or significantlyinterfere with the activity or stability of the PAC, the BBC, the AGAC(in aspects where an AGAC is present), or the activity or stability ofany other excipient(s). Most, generally all, or all of the excipients ofcompositions are typically characterized by one or more classes orcomponents, which typically are defined by the function of suchingredient or component. Examples of the types of components/ingredientsthat can be present in compositions of the invention are described inturn in the following sections, but readers will understand that thesedisclosures can be combined in accordance with more general descriptionsprovided in the Summary, Exemplary Aspects, or other portions of thisdisclosure.

Preservative Component (Preservation Agent(s))

In aspects, compositions provided by the invention comprise apreservative component (which may also be referred to herein as apreservation component). In aspects, the preservative componentcomprises any one or more pharmaceutically acceptable andophthalmologically suitable constituents (e.g., pharmaceuticallyacceptable and ophthalmologically suitable compounds) which detectablyor significantly increase the stability of the composition, detectablyor significantly decrease the degradation of one or more otherconstituents of the composition (over a period of time/under storageconditions—as exemplified elsewhere herein and as is known in the art),detectably or significantly increase the period of time that thecomposition is considered safe and efficacious for use, detectably orsignificantly increases or extends shelf life by maintaining an amountof active pharmaceutical ingredient above a threshold, e.g., a PAC,e.g., bimatoprost base, or a BBC constituent, e.g., timolol maleate,within desirable or acceptable limits, maintaining the level of any oneor more impurities below an acceptable/suitable level, detectably orsignificantly impeding/inhibiting or preventing/restricting growth ofbacteria or other microorganisms in the composition, or any such similarmeasures of composition stability/preservation, or any combination ofsome or all thereof. For example, in aspects, a preservative componentcomprises one or more pharmaceutically acceptable and ophthalmologicallysuitable constituents (e.g., pharmaceutically acceptable andophthalmologically suitable compounds) which aid in maintaining, e.g.,via reducing or preventing microbial contamination, at least about 95%,95%, 97%, 98% or more of the API(s) of the composition, such as, e.g., abimatoprost compound, a timolol compound, or both a bimatoprost compoundand a timolol compound, when stored at about 25° C. +/−2° C. and about40% +/−5% relative humidity; about 40° C. +/−2° C. and not more thanabout 25% relative humidity; about 15° C.-about 27° C. and about 60%relative humidity; about 38° C.-about 42° C. and 75% relative humidity;or when stored under any such condition, or a sequential combination ofsuch conditions, for a period of at least about 1, 3, 6, 9, 12, 18, 24,or, e.g., at least about 36 months. As another example, in aspects, apreservative component comprises one or more pharmaceutically acceptableand ophthalmologically suitable constituents (e.g., pharmaceuticallyacceptable and ophthalmologically suitable compounds) which aid, e.g.,via reducing or preventing microbial contamination, the composition inmaintaining a level of total impurities which is less than about 2.5%after storage at about 25° C. +/−2° C. and about 40% +/−5% relativehumidity; about 40° C. +/−2° C. and not more than about 25% relativehumidity; about 15° C.-about 27° C. and about 60% relative humidity;about 38° C.-about 42° C. and 75% relative humidity; or when storedunder any such condition, or a sequential combination of suchconditions, for a period of at least about 1, 3, 6, 9, 12, 18, 24, or,e.g., at least about 36 months.

In aspects, the preservation component can comprise any one or morepharmaceutically acceptable or ophthalmologically suitable compoundscapable of demonstrating any one or more of the above-described effects(e.g., to a detectable or significant level). In aspects, compositionsherein comprise one or more preservative agents as constituents of apenetration component which maintain the composition in a state (e.g.,with regard to maintenance of the amount of API(s), with regard to thelevel of impurities, or both) which meets requirements for safety andstability established by a recognized regulatory body such as, e.g., theUnited States Food and Drug Administration, when stored at about 25° C.+/−2° C. and about 40% +/−5% relative humidity; about 40° C. +/−2° C.and not more than about 25% relative humidity; about 15° C.-about 27° C.and about 60% relative humidity; about 38° C.-about 42° C. and 75%relative humidity; or when stored under any such condition, or asequential combination of such conditions, for a period of at leastabout 1, 3, 6, 9, 12, 18, 24, or, e.g., at least about 36 months.

In aspects, one or more preservative agents of a preservation componentprovide one or more other detectably or significant functionalactivities, such as for example, providing detectable or significantpenetration enhancement activity, such as, e.g., detectably orsignificantly enhancing the penetration of one or more PAC constituents,e.g., a bimatoprost compound, e.g., bimatoprost base, detectably orsignificantly enhancing the penetration of one or more BBC constituents,e.g., a timolol compound, e.g., a salt of timolol, e.g., timololmaleate, or both a bimatoprost compound and a timolol compound into anocular tissue. In aspects, one or more preservative agents of apreservation component provide detectable or significant solubilizationactivity, such as, e.g., detectably or significantly enhancing thesolubilization of, or detectably or significantly maintaining thesolubilization of, one or more composition constituents, e.g., one ormore PAC constituents, e.g., a bimatoprost compound, e.g., bimatoprostbase, one or more BBC constituents, e.g., a timolol compound, e.g., asalt of timolol, e.g., timolol maleate, or, e.g., detectably orsignificantly maintaining the solubilization of both one or more PACconstituents and one or more BBC constituents.

In aspects, the pharmaceutically acceptable and ophthalmologicallysuitable compositions provided by the invention comprise a preservativecomponent comprising one or more preservation agents present inanti-microbially effective amounts, e.g., an amount capable ofdetectably or significantly inhibiting microbial growth. In aspects, apreservation component of a composition can comprise anyophthalmologically suitable and pharmaceutically acceptable preservativewhich does not detectably or significantly interfere with the requiredfunctionality of any one or more other composition constituents. Inaspects, exemplary constituents of a preservative component comprise,e.g., hydrogen peroxide; sorbic acid; biquanides; quaternary ammoniumsalts such as benzalkonium chloride(s) (abbreviated herein as BKC,though in other literature other abbreviations such as BAC, BAK, or BZKmay be used) and benzethonium chloride; cationic compounds such aschlorhexidine gluconate; p-hydroxybenzoates such as methylp-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate andbutyl p-hydroxybenzoate; alcohol compounds such as chlorobutanol andbenzyl alcohol; sodium dehydroacetate; thiomersal, etc. In aspects, apreservative component can comprise benzalkonium chloride(s) (BKC),wherein the BKC provides detectable or significant penetrationenhancement activity, detectable or significant preservation activity,detectable or significant solubilization effect(s), or any combinationthereof. Benzalkonium chlorides, a class of quaternary ammoniumcompounds suitable for use in compositions herein, include, e.g., knownas alkyl dimethyl benzyl ammonium chlorides (or ADBAC), alkyl dimethyl(phenylmethyl) chlorides, and ammonium alkyl dimethyl benzyl chlorides.

In aspects, compositions provided by the invention comprise apreservation component comprising one or more preservation agents,wherein the preservation component is present in the composition in aconcentration representing about 0.0001% w/v to about 0.02% w/v, suchas, e.g., ˜0.001% w/v-˜0.015% w/v, ˜0.001% w/v-˜0.01% w/v, or ˜0.001%w/v-˜0.008% w/v, ˜0.002% w/v-˜0.02% w/v, ˜0.004% w/v-˜0.02% w/v, or˜0.006% w/v-˜0.02% w/v, e.g., ˜0.0005% w/v-˜0.015% w/v, ˜0.001%w/v-˜0.01% w/v, ˜0.002% w/v-˜0.009% w/v, ˜0.004% w/v-˜0.008% w/v, or˜0.004% w/v-˜0.007% w/v, such as, e.g., about 0.005% w/v of thecomposition. In certain aspects, benzalkonium chloride can be present insuch amounts. In certain aspects, compositions lack benzalkoniumchloride. In certain aspects, compositions provided by the inventionlack any preservative component. In certain aspects, compositionscomprise a preservative component which does not comprise benzalkoniumchloride as a constituent. In aspects, such amounts represent aneffective amount of a preservative/preservation component.

In aspects, a preservation component can comprise a quaternary ammoniumsalt, e.g., benzalkonium chloride, present in the formulation in aconcentration of about 0.0001% w/v to 0.02% w/v, such as about 0.003%w/v to about 0.02% w/v, such as about 0.004% w/v to about 0.02% w/v, orfor example about 0.005% w/v. In some aspects, compositions provided bythe invention comprise benzalkonium chloride in an amount of less thanabout 0.01% w/v. In some aspects, compositions provided by the inventioncomprise benzalkonium chloride in an amount greater than about 0.001%w/v, greater than about 0.002% w/v, greater than about 0.003% w/v, or,e.g., greater than about 0.004% w/v of the composition. In aspects, suchamounts as disclosed here are advantageous in that such amount(s) (1)provides sufficient preservative activity to maintain the stability ofthe compositions according to the composition stability characteristicsdescribed elsewhere herein; (2) provides a detectable or significantenhancement in the penetration of a PAC constituent (e.g., a bimatoprostcompound, e.g., bimatoprost base), a BBC constituent (e.g., a timololcompound, such as a salt of timolol, e.g., timolol maleate), or both aPAC constituent and a BBC constituent, such penetration enhancementdetectable as an increased amount of API penetrating a corneal tissue,detectable as an increased rate of API penetrating a corneal tissue, orboth; or both (1) and (2). In aspects, such amounts as disclosed hereare advantageous in that such amount(s) provide sufficient preservationeffect, provide detectable penetration enhancement effect, do not causea level of ocular irritation upon administration/use by a recipient tocause the recipient to stop use of the composition, or any combinationthereof.

In certain aspects, the invention provides compositions suitable for usein methods of reducing elevated intraocular pressure, such as, e.g.,reducing intraocular pressure associated with glaucoma (e.g., open-angleglaucoma), comprising a reduced amount of benzalkonium chloride (e.g.,an amount of no more than about 0.005% w/v), as benzalkonium chloride isrecognized in the art as a potentially irritating preservative andincorporating one or more non-irritating compounds or compounds innon-irritating amounts such as polysorbate 80 to compensate for thereduction in benzalkonium chloride concentration. In aspects, theinvention provides compositions advantageously capable of achieving acomparable, detectably improved, or significantly improved level ofintraocular pressure reduction using no more than about 0.005% w/v ofbenzalkonium chloride, such as, e.g., about 0.005% w/v benzalkoniumchloride (50 ppm BKC), compared to compositions containing 200 ppm BKC.

In aspects, antimicrobial effective amounts of a preservative may bedetermined by performing preservative efficacy tests or antimicrobialeffectiveness tests. These tests are inter alia described in Chapter 51of the United States Pharmacopeia 29-National Formulary 24 (USP 29-NF24). In aspects, preservative agents of a preservation component areused in an amount within the concentration ranges described in standardreference books like Remington's Pharmaceutical Sciences and Handbook ofPharmaceutical Excipients (e.g., the 23^(rd) Edition thereof—Publishedin 2020).

In certain aspects, the preservation component comprises two or moreconstituents wherein the total concentration/amount of the two or morepreservation component constituents is represented by theconcentrations/amounts provided above. In aspects, the preservationcomponent comprises a single constituent wherein the single constituentis present in an amount represented by the concentrations/amountsprovided above, such as, e.g., benzalkonium chloride in amounts providedabove.

In this and any other ingredient aspect of the invention, the inventionalso can be characterized as comprising a “means” for providing arecited function, here imparting/providing an effective, detectable, orsignificant preservation effect (e.g., increased stability of one ormore constituents of the composition, maintenance of an acceptable levelof impurities during composition storage, increased composition shelflife, etc.) of compositions. In such a respect, any known equivalents ofsuch named agents can also be, e.g., are, incorporated into compositionsor methods of the invention. As with other sections similarly describedherein, any of the components of the invention can be, where suitable,described as means (e.g., the above-described preservationagents/compounds or components can be described as preservation means ormeans for providing effective, detectable, or significant preservationactivity/characteristics to the composition or one or more constituentsof the composition.)

Penetration Enhancer Component (Penetration Enhancer(s))

In certain aspects, compositions provided by the invention comprise apenetration enhancer component (a part of the composition that comprisesone or more penetration enhancer(s)/penetration-enhancing compound(s) ineffective amounts for detectably or significantly enhancing penetrationof other constituents, such as the PAC or one or more compound(s)thereof, the BBC or one or more compound(s) thereof, the AGAC (in aspectwhere such a component is present) or one or more compound(s) thereof,or one or more constituents of each of the PAC, BBC, and AGACcomponents).

In aspects, a penetration enhancer component comprises any one or morepharmaceutically acceptable and ophthalmologically suitable penetrationenhancer(s) (which can be referred to as penetration agents orpenetration enhancing agents/constituents), which provide detectable orsignificant penetration enhancement effect of any one or moreconstituents of the PAC, one or more constituents of the BBC, or one ormore constituents of each of both the PAC and the BBC. In aspects, thepenetration enhancer component (e.g., constituent(s) of the penetrationenhancer component) is any pharmaceutically acceptable andophthalmologically suitable compound(s) capable of (when present in asuitable amount and under suitable conditions) (1) detectably orsignificantly increasing the amount of a PAC constituent, e.g., abimatoprost compound, such as bimatoprost base, which penetrates eyetissue in a given period of time (e.g., the period of time betweendoses, such as within a 24-hour period); (2) detectably or significantlyincreasing the amount of a BBC constituent, e.g., a timolol compound,such as a salt of timolol, e.g., timolol maleate, or both a PACconstituent and a BBC constituent which penetrates eye tissue in a givenperiod of time (e.g., the period of time between doses, such as within a24-hour period); or (3) detectably or significantly increases the amountof a PAC constituent and a BBC constituent which penetrates eye tissuein a given period of time (e.g., the period of time between doses, suchas within a 24-hour period). In aspects, the penetration enhancercomponent or constituent(s) thereof is/are pharmaceutically acceptableand ophthalmologically suitable compound(s) which detectably orsignificantly increase the amount of a PAC constituent (e.g.,bimatoprost base), BBC constituent (e.g., timolol maleate), or both,penetrating eye tissue within a 24-hour, 22-hour, 20-hour, 18-hour,16-hour, 14-hour, 12-hour, 10-hour, 8-hour, 6-hour, 4-hour, 2-hour, or1-hour period of time, such that a detectably or significantly greateramount of the PAC constituent(s) (e.g., a bimatoprost compound, e.g.,bimatoprost base), BBC constituent(s), (e.g., a timolol compound, suchas a salt of timolol, e.g., timolol maleate), or both, is availablewithin the eye tissue for treating the condition of the eye to which thetreatment is directed. In aspects, the presence of a penetrationenhancer component detectably or significantly increases the amount of aPAC constituent (e.g., bimatoprost base), a BBC constituent (e.g., atimolol compound, e.g., a salt of timolol, e.g., timolol maleate), orboth, which penetrates eye tissue over the amount of the same PACconstituent, BBC, or both, present in the same amount in a comparablecomposition lacking the penetration enhancer component.

In aspects, the penetration enhancer component or constituent(s) of thepenetration enhancer component is or are any pharmaceutically acceptableand ophthalmologically suitable compound(s) capable of (1) detectably orsignificantly increasing the rate of penetration into an eye tissue of aPAC constituent, e.g., a bimatoprost compound, such as bimatoprost base,(2) detectably or significantly increasing the rate of penetration intoan eye tissue of a BBC constituent, e.g., a timolol compound, such as asalt of timolol, e.g., timolol maleate, or (3) detectably orsignificantly increasing the rate of penetration into an eye tissue ofboth a PAC constituent and a BBC constituent. In aspects, a constituentof the penetration enhancer component detectably or significantlyincreases the amount of a PAC constituent, BBC constituent, or both aPAC constituent and a BBC constituent penetrating eye tissue per unittime compared to the amount per unit time of the same PAC constituent,BBC constituent, or both the same PAC constituent and the same BBCconstituent present in the same amount in a comparable compositionlacking the penetration component.

In aspects, a penetration enhancer component constituent is a compoundor composition capable of detectably or significantly enhancingpenetration of an active pharmaceutical ingredient, e.g., a PACconstituent (e.g., a bimatoprost compound, e.g., bimatoprost base), aBBC constituent (e.g., a timolol compound, e.g., a salt of timolol,e.g., timolol maleate) or both a PAC constituent and a BBC constituent,in mammalian eye tissue (e.g., in human eye tissue, such as in thetissue of human patients). In some respects, a penetration enhancercomponent constituent can be any ophthalmologically suitable compound ormixture of compounds capable of exerting the effect of increasing thespeed of penetration of an API present in the formulation (e.g., abimatoprost compound, a timolol compound, or both) into ocular cells,e.g., corneal cells, or improving (e.g., increasing) the uptake orretention of an API present in the formulation (e.g., a bimatoprostcompound, a timolol compound, or both) into ocular tissue or ocularcells. In aspects, a penetration enhancer detectably or significantlyenhances penetration of an API, e.g., a bimatoprost compound, e.g.,bimatoprost base, or, e.g., a timolol compound, e.g., timolol maleate,or both a bimatoprost compound and a timolol compound, into oculartissue by at least about 10%, at least about 20%, at least about 30%, atleast about 40%, at least about 50%, at least about 60%, at least about70%, at least about 80%, at least about 90%, or by at least about 100%,such as at least approximately 120%, at least approximately 140%, atleast approximately 160%, at least approximately 180%, or at leastapproximately 200% or even more, over similar (e.g., at least generallythe same, at least substantially the same, at least essentially thesame, essentially the same, or the same) formulations (in terms of thepresence of API(s), excipient(s), amount(s) of any or all thereof orcombinations of such characteristic(s)) lacking such a penetrationenhancer. In aspects, penetration can be measured or reflect the amountof API(s) in a tissue, such as ocular tissue; can reflect thepenetration of the API(s) throughout the tissue (e.g., the averageamount throughout an entire tissue, the minimum amount throughout thetissue, or both, such as any of the amounts described herein or thepresence of significant or detectable amount(s) of the API(s) asdistributed through the tissue); or both.

In one aspect, the invention provides a pharmaceutically acceptable andophthalmologically suitable composition comprising a bimatoprostcompound, a timolol compound, and benzalkonium chloride, wherein, e.g.,the concentration of the bimatoprost compound is about 0.005% w/v toabout 0.02% w/v, the concentration of the timolol compound is about0.25% w/v to about 0.5% w/v, and the concentration of the benzalkoniumchloride is about 0.003% w/v to about 0.007% w/v. In one specificexemplary aspect, the invention provides such a composition wherein thecomposition further comprises a penetration enhancer component separatefrom any penetration enhancement effect provided by the benzalkoniumchloride, e.g., a penetration enhancer component comprising at least oneconstituent other than benzalkonium chloride. In further exemplaryaspects, such a penetration enhancer component represents at least about0.1% w/v, ≥˜0.2% w/v, ≥˜0.3% w/v, ≥˜0.4% w/v, ≥˜0.5% w/v, ≥˜0.6% w/v,≥˜0.7% w/v, ≥˜0.8% w/v, ≥˜0.9% w/v, or, e.g., ≥˜1% w/v of thecomposition.

In certain aspects, compositions herein do not comprise a penetrationenhancer component. In certain aspects, a composition provided herein isprovided in the form of a gel. In some aspects, the gel compositioncomprises a penetration enhancer component. In alternative aspects, acomposition provided in the form of a gel does not comprise apenetration enhancer component. In aspects, a penetration enhancercomponent can comprise one or more constituents which is notbenzalkonium chloride. In aspects, a penetration enhancer component cancomprise one or more constituents which is not benzalkonium chloride,however benzalkonium chloride is present in the composition, and thebenzalkonium chloride may in present in the composition in a sufficientamount so as to provide detectable or significant penetrationenhancement effect, such that the benzalkonium chloride can also beconsidered a constituent of the penetration enhancer component.

In aspects, a penetration enhancer component of a composition cancomprise any ophthalmologically suitable and pharmaceutically acceptablepenetration enhancing agent which does not detectably or significantlyinterfere with the required functionality of any one or more othercomposition constituents, such as any one or more APIs or one or moreexcipients. In aspects, a penetration enhancer component can comprise atleast one constituent characterizable as a non-ionic surfactant havingan HLB value of at least about 12, such as ≥˜12.5, ≥˜13, ≥˜13.5, ≥˜14,≥˜14.5, ≥˜15, ≥˜15.5, ≥˜16, ≥˜16,5, ≥˜17, ≥˜17.5, or, e.g., ≥˜18. Inaspects, the penetration enhancer component comprises at least one agentselected from a group comprising a polyoxyl-n-castor oil, apolyoxyethylene, a polyoxypropylene, and/or any combination or blockpolymer thereof. In aspects, the penetration enhancer component cancomprise, mostly comprise, generally consist of, substantially consistof, consist essentially of, or consist of a non-ionic penetrationenhancer constituent (e.g., polysorbate 80).

In aspects, exemplary constituents of a penetration enhancer componentcan comprise, e.g., a protein/peptide penetration enhancing agent (e.g.,poly-arginine or polyserine). In aspects, exemplary constituents of apenetration enhancer component can comprise, e.g., a non-protein/peptidepenetration enhancing agent. In aspects, exemplary constituents of apenetration enhancer component comprise, e.g., one or more of (e.g., inaspects a combination of two or more of pharmaceutically acceptable andophthalmologically suitable polyoxyethylene sorbitan fatty acidester(s), tocopheryl polyethylene glycol succinate (TPGS),poly-arginine, polyserine, tromethamine (tris), sesame seed oil or oilshaving similar compositions and functional characteristics suitable forophthalmic use, etc. Exemplary polyoxyethylene sorbitan fatty acidesters include but not limited to polyoxyethylene sorbitan laurate(polysorbate 20), polyoxyethylene sorbitan palmitate (polysorbate 40), apolyoxyethylene sorbitan stearate (polysorbate 60), a polyoxyethylenesorbitan tri stearate (polysorbate 65). In some aspects thepolyoxyethylene sorbitan fatty acid ester can be a polyoxyethylenesorbitan oleate/polyoxyethylene sorbitan mono-oleate ester (e.g.,polysorbate 80). In certain aspects, compositions provided by theinvention can comprise a penetration enhancer component comprisingeffective amounts of one or more of one or more polyoxyethylene sorbitanfatty acid ester(s), tocopheryl polyethylene glycol succinate (TPGS),poly-arginine, or polyserine. In certain aspects, compositions providedby the invention can comprise a penetration enhancer componentcomprising effective amounts of one or more of one or more of thecompounds selected from the group consisting of polyoxyethylene sorbitanfatty acid ester(s), tocopheryl polyethylene glycol succinate (TPGS),poly-arginine, and polyserine.

In aspects, additional compounds suitable for use in the presentinvention for increasing the penetration of an API of the compositionwithin ocular tissue also can include quaternary ammonium compounds,such as, e.g., an ophthalmologically suitable quaternary ammonium salt.Quaternary ammonium compounds include ammonium salts in which organicradicals have been substituted for all four hydrogens of the originalammonium cation. Such compounds typically have a structure comprising acentral nitrogen atom which is joined to four organic radicals and oneacid radical. The organic radicals may be alkyl, aryl, or aralkyl, andthe nitrogen can be part of a ring system. Examples of such compoundsinclude benzalkonium chloride (e.g., CAS RN: 8001-54-5); benzethoniumchloride CAS 121-54-0; cetalkonium chloride (e.g., CAS 122-18-9);cetrimide (e.g., CAS 8044-71-1); cetrimonium bromide (e.g., CAS57-09-0); cetylpyridinium chloride (e.g., CAS 123-03-5); andstearalkonium chloride (e.g., CAS 122-19-0), provided that typically thequaternary ammonium compound included in any composition provided hereinis of a nature and amount that is ophthalmologically safe. Suchcompounds can, e.g., in aspects also provide a detectably or significantpreservation effect as described above. Therefore, in aspects, such acompound may be both a constituent of a preservative component and apenetration enhancer component.

In aspects, a penetration enhancer component can comprise benzalkoniumchloride, benzethonium chloride, benzyltrimethylammonium chloride (alsoknown as Triton B or trimethylbenzylammonium hydroxide), orlauryltrimethylammonium chloride (also known as dodecyltrimethylammoniumchloride). In some embodiments, the ophthalmic formulations of theinvention lack any quaternary ammonium salt.

In some aspects, formulations described herein also or alternativelycomprise polyoxyl n castor oils (n=35-40) or polyoxyl hydrogenatedcastor oils, such as for example polyethoxylated castor oils, e.g.,polyoxyl 35 castor oil (e.g., Cremophor EL), polyoxyl 40 castor oil(e.g., Marlowet 40, Emulgin RO 40), a polyoxyethylene hydrogenatedcastor oil (such as, e.g., polyoxyethylene hydrogenated castor oil10/polyoxyl 10 hydrogenated castor oil, polyoxyethylene hydrogenatedcastor oil 40/polyoxyl 40 hydrogenated castor oil (Cremophor RH 40),polyoxyethylene hydrogenated castor oil 50/polyoxyl 50 hydrogenatedcastor oil, and polyoxyethylene hydrogenated castor oil 60/polyoxyl 60hydrogenated castor oil (Cremophor RH 60)). In aspects, one suitablepolyoxyl castor oil is polyoxyl-35-castor oil. The term “cremophor” canbe used in this disclosure as a convenient reference to mean any suchtype of castor oil-related compounds/compositions, groups of two or more(as a class), combinations thereof, and equivalents thereof.

In aspects, a penetration enhancer component can comprise, e.g., apolyoxyethylene polyoxypropylene glycol, e.g., a polyoxyethylene (160)polyoxypropylene (30) glycol (Pluronic F68), a polyoxyethylene (42)polyoxypropylene (67) glycol (Pluronic P123), a polyoxyethylene (54)polyoxypropylene (39) glycol (Pluronic P85); a polyoxyethylene (196)polyoxypropylene (67) glycol (Pluronic F127) and a polyoxyethylene (20)polyoxypropylene (20) glycol (Pluronic L-44); or a polyethyleneglycolfatty acid ester, such as mono-lauric acid polyethyleneglycol,monostearin acid ethylene glycol, monostearin acid polyethyleneglycol,the mono-oleic acid polyethyleneglycol, monostearin acid ethyleneglycol, an ethylene glycol distearate, the distearic acidpolyethyleneglycol, and diiso stearic-acid polyethyleneglycol. Inaspects, a suitable compound is polyoxyl 40 stearate. In other aspects,a penetration enhancer component can comprise tyloxapol. In furtheraspects, poloxamers (block copolymers) of certain examples above, suchas a polyoxyethylene-polyoxypropylene block copolymer (e.g., PluronicF-68 from BASF) and polaxamines (copolymers of three long chains ofethylene oxide and a single chain of propylene oxide that are used asnonionic surfactants) are compounds suitable for penetration enhancercomponents of compositions herein. In certain aspects, compositions lackany constituent characterizable as a poloxamer, e.g., characterizable asa block copolymer (e.g., in certain aspects, compositions lack anypoloxamer/block copolymer).

As noted above, any ingredient/constituent/excipient described hereintypically is present in an effective amount (an amount that alone or incombination with other present agents provides a measurable orsignificant desired effect, such as penetration enhancement). Anyingredient/constituent described here with respect acomponent/composition comprising that ingredient/component, again,provides implicit support for corresponding aspects in which thedescribed component mostly comprises, generally consists of,substantially consists of, consists essentially of, or consists only ofthe recited constituent, type of constituent, etc.

In aspects, compositions provided by the invention comprise apenetration enhancer component comprising one or more penetrationenhancing agents, wherein the penetration enhancer component is presentin the composition in a concentration representing about 0.01% w/v-about1% w/v, such as, e.g., ˜0.05% w/v-˜0.5% w/v, ˜0.7% w/v-˜0.3% w/v, or,e.g., ˜0.1% w/v-˜0.2% w/v such as, e.g., ˜0.185% w/v of the composition.

In aspects, compositions provided by the invention comprise apenetration enhancer component comprising one or more penetrationenhancing agents, wherein the penetration enhancer component is presentin the composition in a concentration representing about 0.05% w/v toabout 5% w/v of the composition, such as, e.g., ˜0.1% w/v-˜5% w/v,˜0.15% w/v-˜5% w/v, ˜0.2% w/v-˜5% w/v, or ˜0.25% w/v-˜5% w/v, such as˜0.05% w/v-˜5% w/v, ˜0.05% w/v-˜4.5% w/v, ˜0.05% w/v-˜4% w/v, ˜0.05%w/v-˜3.5% w/v, ˜0.05% w/v-˜3% w/v, ˜0.05% w/v-˜2.5% w/v, ˜0.05% w/v-˜2%w/v, ˜0.05% w/v-˜1.5% w/v, or ˜0.05% w/v-˜1% w/v, such as ˜0.1% w/v-˜4%w/v, ˜0.15% w/v-˜3% w/v, ˜0.2% w/v-˜2.5% w/v, ˜0.25% w/v-˜2.5% w/v,˜0.2% w/v-˜1% w/v, or ˜0.2% w/v-˜0.5% w/v, such as for example about0.25% w/v of the composition, about 0.5% w/v of the composition, or,e.g., about 1% w/v of the composition. In aspects, such amountsrepresent an effective amount of a penetration enhancer component.

In aspects, compositions provided by the invention comprise apenetration enhancer component comprising one or more penetrationenhancing agents, wherein the penetration enhancer component is presentin the composition in a concentration representing about 0.005% w/v toabout 0.01% w/v of the composition, such as, e.g., ˜0.005% w/v-˜0.009%w/v, or ˜0.005% w/v-˜0.008% w/v, such as, e.g., ˜0.006% w/v-˜0.01% w/vor ˜0.007% w/v-˜0.01% w/v, as in, e.g., about ˜0.006% w/v-˜0.009% w/v or˜0.007% w/v-˜0.008% w/v of the composition, such as, e.g., ˜0.005% w/vof the composition. In aspects, such amounts represent an effectiveamount of a penetration enhancer component.

In aspects, compositions provided by the invention comprise apenetration enhancer component comprising one or more penetrationenhancing agents, wherein the penetration enhancer component is presentin the composition in a concentration representing about 0.25% w/v-about5% w/v of the composition, such as, e.g., ˜0.25% w/v-˜2.5% w/v of thecomposition, e.g., ˜0.5% w/v-˜2% w/v, ˜0.5% w/v-˜1.5% w/v, or, e.g.,˜0.8% w/v-˜1.1% w/v of the composition, such as for example ˜1% w/v ofthe composition. In aspects, such amounts represent an effective amountof a penetration enhancer component.

In certain aspects, the penetration enhancer component comprises two ormore constituents wherein the total concentration/amount of the two ormore penetration enhancer component constituents is represented by theconcentrations/amounts provided above. For example, in some exemplaryaspects, compositions comprise a penetration enhancer componentcomprising, e.g., polysorbate 80, cremophor EL, or, e.g., TPGS, presentin an amount representing ˜0.05% w/v-˜5% w/v, ˜0.1% w/v-˜4% w/v, ˜0.15%w/v-˜3% w/v, ˜0.2% w/v-˜2% w/v, ˜0.2% w/v-˜1% w/v, or ˜0.2% w/v-˜0.5%w/v, such as for example about 1% w/v of the composition, and,optionally further, a benzalkonium chloride in an amount representingabout 0.001% w/v to about 0.01% w/v of the composition, such as, e.g.,˜0.002% w/v-˜0.008% w/v or ˜0.004% w/v-˜0.006% w/v of the composition,such as ˜0.005% w/v of the composition. In aspects, compositions cancomprise a penetration enhancer component comprising two or moreconstituents, such as, e.g., one of polysorbate 80, tromethamine (tris),cremophor EL, poly-arginine, or polyserine, and benzalkonium chloride,wherein the penetration component comprises about 0.05% w/v to about 2%w/v, such as about 0.1% w/v-˜1.8% w/v, such as, e.g., about 0.1%w/v-˜0.5% w/v, about 0.2% w/v and about 1.4% w/v of the composition,such as, e.g., about 0.2% w/v or about 1% w/v of the composition orabout 1.005% w/v of the composition. This principle can be applied tocombinations of any of the specific penetration enhancers describedherein, any combination of classes of penetration enhancers, or anymixture thereof, and can include three or more of such compounds/classesof compounds. For example, compositions can comprise polysorbate 80,benzalkonium chloride, and, e.g., cremophor, wherein each provide, orthe combination thereof provides, or both, detectable or significantpenetration enhancement effect(s). In another example, compositions cancomprise, e.g., one or more of polysorbate 80, cremophor, or TPGS, alongwith benzalkonium chloride. In another example, compositions cancomprise, e.g., one or more of polysorbate 80, cremophor, or TPGS, alongwith benzalkonium chloride and tromethamine (tris). In aspects, suchamounts provided in this paragraph represent an effective amount of apenetration enhancer component.

In aspects, the penetration enhancer component comprises/consistsessentially of/consists of a single constituent wherein, in aspects, thesingle constituent is present in an amount represented by theconcentrations/amounts provided above.

In certain aspects, the penetration enhancer componentcomprises/consists essentially of (and, of course, by implication,alternatively consists of) two or more polyoxyethylene sorbitan fattyacid esters wherein the total amount of the two or more polyoxyethylenesorbitan fatty acid esters is represented by the concentrations/amountsabove.

In aspects, the penetration enhancer component comprises/consistsessentially of a single polyoxyethylene sorbitan fatty acid ester,wherein the total amount of the single polyoxyethylene sorbitan fattyacid ester is represented by the concentrations/amounts provided above.In certain aspects, the penetration enhancer component comprises asingle constituent, the single constituent being a polyoxyethylenesorbitan fatty acid ester, such as, e.g., polysorbate 80, wherein thesingle polyoxyethylene sorbitan fatty acid ester, e.g., polysorbate 80,is, e.g., present in an amount representing ˜0.05% w/v-˜5% w/v, ˜0.1%w/v-˜4% w/v, ˜0.15% w/v-˜3% w/v, ˜0.2% w/v-˜2% w/v, ˜0.2% w/v-˜1.5% w/v,or ˜0.5% w/v-˜1.2% w/v, such as for example about 1% w/v of thecomposition. In aspects, such amounts represent an effective amount of apenetration enhancer component constituent.

In aspects, a single constituent of the penetration enhancer componentis/consists essentially of polysorbate 80. In aspects, a singleconstituent of the penetration enhancer component is/consistsessentially of cremophor EL. In aspects, a single constituent of thepenetration enhancer component is/consists essentially of TPGS. Inaspects, the penetration enhancer component is/consists essentially ofpolysorbate 80, cremophor EL, or TPGS in combination with benzalkoniumchloride. In some embodiments, the penetration enhancer component ofcompositions further comprises tromethamine (tris).

In certain alternative aspects, the penetration enhancer componentcomprises a single constituent, wherein the single constituent is aquaternary ammonium compound, e.g., a quaternary ammonium salt, e.g.,benzalkonium chloride, e.g., being present in an amount representingabout 0.001% w/v to about 0.01% w/v of the composition, such as, e.g.,˜0.002% w/v-˜0.009% w/v, ˜0.003% w/v-˜0.008% w/v, ˜0.004% w/v-˜0.007%w/v, or ˜0.004% w/v-˜0.006% w/v of the composition, e.g., ˜0.005% w/v ofthe composition. In aspects, such amounts represent an effective amountof benzalkonium chloride. In aspects, the compositions provided by theinvention comprise no penetration enhancer component. In aspects, thecompositions provided by the invention comprise no penetration enhancercomponent other than benzalkonium chloride. In aspects, compositionsprovided by the invention comprise benzalkonium chloride in an amountwhich does not provide detectable or significant penetration enhanceractivity. According to certain aspects of the invention, compositionscan comprise at least one additional ophthalmologically suitablequaternary ammonium salt, selected from a group comprising benzethoniumchloride, benzyltrimethylammonium chloride, lauryl trimethyl ammoniumchloride, or any combination thereof which each alone or in combinationprovide a detectable or significant increase in penetration of a PACconstituent, a BBC constituent, or one or more constituents of each ofthe PAC and the BBC. In another aspect, compositions are free of anypenetration enhancer(s) other than benzalkonium chloride characterizableas a quaternary ammonium salt. In certain aspects, compositions are freeof any penetration enhancer(s) characterizable as a quaternary ammoniumsalt.

In aspects, one or more constituents of the penetration enhancercomponent can further provide one or more additional detectable orsignificant functionalities to a formulation/composition, such as, forexample, a detectable or significant solubilization effect (such as isdescribed elsewhere herein), detectable or significant demulcent effect,detectable or significant preservation effect, or any combinationthereof. In aspects, one or more constituents of the penetrationenhancer component can further provide a preservation/preservativeeffect. In one aspect, a penetration enhancing agent of the penetrationenhancer component also provides a detectable or significantsolubilization effect. In one aspect, a penetration enhancing agent ofthe penetration enhancer component also provides a detectable orsignificant demulcent effect. In one aspect, a penetration enhancingagent of the penetration enhancer component also provides both adetectable or significant solubilization enhancement effect and adetectable or significant demulcent effect. In one aspect, a penetrationenhancing agent of the penetration enhancer component also provides adetectable or significant preservation effect and a detectable orsignificant solubilization effect. In certain aspects, a penetrationenhancing agent of the penetration enhancer component does not provide asolubilization effect, does not provide a preservation effect, does notprovide a demulcent effect, or does not provide any combination of suchadditional effects. That is, in aspects, a penetration enhancer and asolubilizing agent, or a penetration enhancer and a demulcent, or, e.g.,a penetration agent and a preservation agent can be differing compounds.

As stated above, in aspects, compositions provided by the invention cancomprise one or more penetration enhancers (e.g., penetration enhancercomponent constituents) in an amount of about, e.g., 0.001% w/v-about2.7% w/v, about 1% w/v-about 3% w/v, or, e.g., about 2% w/v-about 5%w/v. In aspects, such amounts represent an effective amount of apenetration enhancer. In aspects, such amounts are advantageous in thatsuch an amount provides a detectable or significant increase in theamount of API, e.g., the amount of a bimatoprost compound (e.g.,bimatoprost base), the amount of a timolol compound (e.g., a salt oftimolol, e.g., timolol maleate), or both the amount of a bimatoprostcompound and timolol compound, which penetrates ocular tissue peradministration or also or alternatively the rate at which such one ormore compounds penetrates ocular tissue upon administration. In aspects,such amounts are advantageous in that such an effect can be achievedwithout the user experiencing one or more side effects which cause theuse to discontinue use of the composition.

In this and any other ingredient aspect of the invention, the inventionalso can be characterized as comprising a “means” for providing arecited function, here imparting/providing an effective, detectable, orsignificant penetration effect to one or more constituents ofcomposition(s) of the invention. In such a respect, any knownequivalents of such named agents can also be, e.g., are, incorporatedinto compositions or methods of the invention. As with other sectionssimilarly described herein, any of the components of the invention canbe, where suitable, described as means (e.g., the above-describedpenetration enhancement agents/compounds or components can be describedas penetration enhancer means (or penetration means) or means forproviding effective, detectable, or significant penetrationactivity/characteristics to one or more constituents of thecomposition).

Solubilization Component (Solubilizing Agent(s))

In aspects, compositions provided by the invention comprise asolubilization component. In aspects, the solubilization componentcomprises any one or more pharmaceutically acceptable andophthalmologically suitable constituents (e.g., pharmaceuticallyacceptable and ophthalmologically suitable compounds) which detectablyor significantly increase the solubilization of one or more otherconstituents of the composition, detectably or significantly increasethe period of time that one or more other constituents of thecomposition remain solubilized, or both. In aspects, the solubilizationcomponent can comprise any one or more pharmaceutically acceptable orophthalmologically suitable compounds capable of demonstrating such aneffect. In aspects, a solubilizing agent of a solubilization componentcan be a surfactant, e.g., demonstrating detectable or significantsurfactant properties/functions, e.g., in the context of the associatedcomposition/formulation. In aspects, a solubilization component of acomposition (e.g., a surfactant) can comprise any ophthalmologicallysuitable and pharmaceutically acceptable solubilizing agent (or, e.g.,surfactant) which does not detectably or significantly interfere withthe required functionality of any one or more other compositionconstituents.

In aspects, one or more constituents of the solubilization component canfurther provide one or more additional detectable or significantfunctionalities, such as, for example, detectable or significantpenetration enhancement effect(s) (such as is described elsewhereherein), detectable or significant demulcent effect(s), or both. In oneaspect, a solubilizing agent of the solubilizing component also providesdetectable or significant penetration enhancement effect(s). In oneaspect, a solubilizing agent of the solubilizing component also providesdetectable or significant demulcent effect(s). In one aspect, asolubilizing agent of the solubilizing component also provides bothdetectable or significant penetration enhancement effect and detectableor significant demulcent effect. In certain aspects, a solubilizingagent of the solubilizing component does not provide either apenetration enhancement effect or a demulcent effect. In aspects, apenetration enhancer and a solubilizing agent, or a penetration enhancerand a demulcent, can be different compounds, or a combination of allthree agents can be present due to the inclusion of two compounds orthree separate compounds in the composition, in the former case wheresuch a compound is a dual class excipient (e.g., as is the case with apenetration enhancer that also is a preservative).

In aspects, compositions comprise a penetration enhancer componentcomprising one or more constituents which provide detectable orsignificant solubilizing activity. Therefore, in aspects, compositionscan comprise a plurality of solubilizing agents, such as, for example, afirst solubilizing agent which further provides detectable orsignificant penetration enhancement activity (e.g., a polyoxyethylenesorbitan fatty acid ester, such as polysorbate 80), TPGS, or also oralternatively a polyoxyl hydrogenated castor oils, such as for exampleone or more polyethoxylated castor oils, such as cremophor EL, inaddition to a second solubilizing agent, such as, e.g., tromethamine.

In aspects, exemplary constituents of a solubilization componentcomprise, e.g., one or more of pharmaceutically acceptable andophthalmologically suitable polyoxyethylene sorbitan fatty acid esters,tocopheryl polyethylene glycol succinate (TPGS), poly-arginine,polyserine, tromethamine (tris), sesame seed oil or oils having similarcompositions and functional characteristics suitable for ophthalmic use,etc. Exemplary polyoxyethylene sorbitan fatty acid esters includepolyoxyethylene sorbitan laurate (polysorbate 20), polyoxyethylenesorbitan palmitate (polysorbate 40), a polyoxyethylene sorbitan stearate(polysorbate 60), a polyoxyethylene sorbitan tri stearate (polysorbate65). In some aspects the polyoxyethylene sorbitan fatty acid ester canbe a polyoxyethylene sorbitan oleate/polyoxyethylene sorbitanmono-oleate ester (e.g., polysorbate 80). In certain aspects,constituents of a solubilization component can comprise, e.g., one ormore polyethoxylated castor oils, such as, e.g., polyethoxylated castoroils characterizable as cremophor(s).

In aspects, one or more compounds provided in the section entitled“Penetration Enhancer Component (Penetration Enhancer(s))” also havesolubilization properties, and, thus, may be considered a constituent ofa solubilization component.

In aspects, compositions provided by the invention comprise asolubilization component comprising one or more solubilizing agents,wherein the solubilization component is present in the composition in aconcentration representing about 0.05% w/v to about 5% w/v of thecomposition, such as, e.g., ˜0.1% w/v-˜5% w/v, ˜0.15% w/v-˜5% w/v, ˜0.2%w/v-˜5% w/v, or, e.g., ˜0.25% w/v-˜5% w/v of the composition.

In aspects, compositions provided by the invention comprise asolubilization component comprising one or more solubilizing agents,wherein the solubilization component is present in the composition in aconcentration representing about 0.05% w/v to about 5% w/v of thecomposition, such as, e.g., ˜0.05% w/v-˜4.5% w/v, ˜0.05% w/v-˜4% w/v,˜0.05% w/v-˜3.5% w/v, ˜0.05% w/v-˜3% w/v, ˜0.05% w/v-˜2.5% w/v, ˜0.05%w/v-˜2% w/v, ˜0.05% w/v-˜1.5% w/v, or ˜0.05% w/v-˜1% w/v of thecomposition.

In aspects, compositions provided by the invention comprise asolubilization component comprising one or more solubilizing agents,wherein the solubilization component is present in the composition in aconcentration representing about 0.05% w/v to about 5% w/v of thecomposition, such as, e.g., ˜0.1% w/v-˜4% w/v, ˜0.15% w/v-˜3% w/v, ˜0.2%w/v-˜2% w/v, ˜0.3% w/v-˜1.5% w/v, or ˜0.4% w/v-˜1% w/v, such as forexample about 0.1% w/v, ˜0.2% w/v, ˜0.3% w/v, ˜0.4% w/v, ˜0.5% w/v,˜0.6% w/v, ˜0.7% w/v, ˜0.8% w/v, ˜0.9% w/v, ˜1% w/v, ˜1.1% w/v, or,e.g., ˜1.2% w/v of the composition.

In certain aspects, the solubilization component comprises two or moreconstituents wherein the total concentration/amount of the two or moresolubilization component constituents is represented by theconcentrations/amounts provided above. For example, in some aspects,compositions an comprise a solubilization component comprising aconstituent characterizable as a polyethoxylated castor oil andtromethamine. In aspects, compositions can comprise, e.g., apolyethoxylated castor oil, e.g., cremophor, TPGS, or, e.g., polysorbate80 in an amount representing about 0.1% w/v to about 5% w/v, such as,e.g., ˜0.5% w/v-˜4% w/v, or ˜1% w/v-˜3% w/v, such as, e.g., about 0.25%w/v-about 2.5% w/v of the composition, e.g., ˜1% w/v of the compositionor also or alternatively, e.g., tromethamine (tris) in an amountrepresenting ˜0.1% w/v-0.2% w/v, e.g., ˜0.185% w/v of the composition.In aspects, compositions can comprise, e.g., tromethamine (tris), in anamount representing about 0.1% w/v to about 0.5% w/v, such as, e.g.,˜0.1% w/v-˜0.4% w/v, ˜0.1% w/v-˜0.3% w/v, or ˜0.1% w/v-˜0.2% w/v, suchas, e.g., about 0.185% w/v of the composition. In aspects, compositionscan comprise a solubilization component comprising at least twosolubilization constituents, wherein the total amount of the at leasttwo solubilization constituents represents about 0.2% w/v to about 5%w/v of the composition, such as, e.g., ˜0.3% w/v-˜4% w/v, ˜0.4% w/v-˜3%w/v, ˜0.5% w/v-˜2% w/v, or, e.g., ˜1% w/v-˜1.5% w/v, e.g., ˜1.185% w/vof the composition.

In aspects, the solubilization component comprises a single constituentwherein the single constituent is present in an amount represented bythe concentrations/amounts provided above. In certain aspects, thesolubilization component comprises two or more polyoxyethylene sorbitanfatty acid esters wherein the total amount of the two or morepolyoxyethylene sorbitan fatty acid esters is represented by theconcentrations/amounts provided above (or alternatively each is presentin the amounts provided above). In aspects, the solubilization componentcomprises a single polyoxyethylene sorbitan fatty acid ester, whereinthe total amount of the single polyoxyethylene sorbitan fatty acid esteris represented by the concentrations/amounts provided above. In certainaspects, the solubilization component comprises a single constituentwhich further provides detectable or significant penetration enhancementactivity, the single constituent being a polyoxyethylene sorbitan fattyacid ester, such as, e.g., polysorbate 80, wherein, in aspects, thesingle polyoxyethylene sorbitan fatty acid ester, e.g., polysorbate 80,is present in an amount representing ˜0.05% w/v-˜5% w/v, ˜0.1% w/v-˜4%w/v, ˜0.15% w/v-˜3% w/v, ˜0.25% w/v-˜2.5% w/v, ˜0.2% w/v-˜2% w/v, ˜0.2%w/v-˜1.5% w/v, or ˜0.2% w/v-˜0.5% w/v, such as for example about 1% w/vof the composition. In aspects, the solubilization component furthercomprises a single constituent, e.g., an additional single constituent,wherein the single constituent is present in an amount represented bythe concentrations/amounts provided above, such as, e.g., tromethaminein an amount of about 0.01% w/v-about 1% w/v, such as, e.g., ˜0.05%w/v-˜0.5% w/v, ˜0.7% w/v-˜0.3% w/v, or, e.g., ˜0.1% w/v-˜0.2% w/v suchas, e.g., ˜0.185% w/v of the composition.

In aspects, such amounts of a solubilization component, solubilizationcomponent constituents, or both, disclosed in this section represent aneffective amount of a solubilization component, solubilization componentconstituent, or both. In certain aspects, composition(s) herein lack asolubilization component.

In this and any other ingredient aspect of the invention, the inventionalso can be characterized as comprising a “means” for providing arecited function, here imparting/providing an effective, detectable, orsignificant solubilization effect (e.g., increased solubilization) toone or more constituents of composition(s) of the invention. In such arespect, any known equivalents of such named agents can also be, e.g.,are, incorporated into compositions or methods of the invention. As withother sections similarly described herein, any of the components of theinvention can be, where suitable, described as means (e.g., theabove-described solubilization agents/compounds or components can bedescribed as solubilization means or means for providing effective,detectable, or significant solubilization activity/characteristics toone or more constituents of the composition.)

Combination Solubilization/Penetration Enhancer Component (SolubilizingAgent(s)/Penetration Enhancer(s))

In certain aspects, a single ingredient of compositions provided by theinvention can be a constituent of both a penetration enhancer componentand a solubilization component. E.g., in aspects, a single ingredient ofcompositions provided by the invention can be characterized as capableof providing both detectable and significant solubilization effect anddetectable and significant penetration enhancement effect, such affectsbeing described above in each of the solubilization component andpenetration enhancer component sections, respectively. Therefore, inaspects, one or more compounds provided in the section entitled“Penetration Enhancer Component (Penetration Enhancer(s)),” havingpenetration enhancing effect(s), can, in aspects be interpreted as beingrepeated in the section entitled “Solubilization Component (SolubilizingAgent(s)),” having solubilization effect(s). Further, in aspects, one ormore compounds provided in the section entitled “SolubilizationComponent (Solubilizing Agent(s)),” having solubilization effect(s),can, in aspects, be interpreted as being repeated in the sectionentitled “Penetration Enhancer Component (Penetration Enhancer(s)),”having penetration enhancing effect(s). In certain aspects, aconstituent of the penetration enhancer component can act as only apenetration enhancer and provide no detectable or significantsolubilization effect. Similarly, in aspects, a constituent of thesolubilization component can act as only a solubilizer and provide nodetectable or significant penetration enhancement effect.

In aspects, one or more ingredients providing both a detectable orsignificant penetration enhancing effect and a detectable or significantsolubilization effect can further provide detectable or significantdemulcent effect. In certain aspects, an ingredient providing both adetectable or significant penetration enhancing effect and a detectableor significant solubilization effect does not provide detectable orsignificant demulcent effect. That is, in aspects, a single ingredientproviding both penetration enhancer functionality and solubilizingfunctionality, and a demulcent, can be different/differing compounds.

Exemplary combination solubilizer and penetration enhancer compoundsinclude, e.g., one or more of pharmaceutically acceptable andophthalmologically suitable polyoxyethylene sorbitan fatty acid esters,tocopheryl polyethylene glycol succinate (TPGS), poly-arginine,polyserine, tromethamine (tris), sesame seed oil or oils having similarcompositions and functional characteristics suitable for ophthalmic use,etc. Exemplary polyoxyethylene sorbitan fatty acid esters include butnot limited to polyoxyethylene sorbitan laurate (polysorbate 20),polyoxyethylene sorbitan palmitate (polysorbate 40), a polyoxyethylenesorbitan stearate (polysorbate 60), or a polyoxyethylene sorbitan tristearate (polysorbate 65). In some aspects the polyoxyethylene sorbitanfatty acid ester can be a polyoxyethylene sorbitanoleate/polyoxyethylene sorbitan mono-oleate ester (e.g., polysorbate80). Other exemplary combination solubilizer and penetration enhancercompounds include, e.g., polyethoxylated castor oil(s), e.g., acremophor (such as, e.g., cremophor EL).

In some aspects, compositions comprise, e.g., benzalkonium chloride andone or more of, e.g., polysorbate 80, cremophor EL, and TPGS.

In some aspects, compositions comprise, e.g., benzalkonium chloride; oneor more of, e.g., polysorbate 80, cremophor EL, and TPGS; andtromethamine (tris).

In aspects, compositions provided by the invention comprise a singleingredient providing both penetration enhancement and solubilizationfunctionality, wherein the single ingredient is present in thecomposition in a concentration representing about 0.05% w/v to about 5%w/v of the composition, such as, e.g., ˜0.1% w/v-˜5% w/v, ˜0.15% w/v-˜5%w/v, ˜0.2% w/v-˜5% w/v, or ˜0.25% w/v-˜5% w/v, such as ˜0.05% w/v-˜5%w/v, ˜0.05% w/v-˜4.5% w/v, ˜0.05% w/v-˜4% w/v, ˜0.05% w/v-˜3.5% w/v,˜0.05% w/v-˜3% w/v, ˜0.05% w/v-˜2.5% w/v, ˜0.05% w/v-˜2% w/v, ˜0.05%w/v-˜1.5% w/v, or ˜0.05% w/v-˜1% w/v, such as ˜0.1% w/v-˜4% w/v, ˜0.15%w/v-˜3% w/v, ˜0.2% w/v-˜2% w/v, ˜0.2% w/v-˜1% w/v, or ˜0.2% w/v-˜0.5%w/v, such as for example about 1% w/v of the composition. In certainaspects, the single ingredient is a polyoxyethylene sorbitan fatty acidester, such as, e.g., polysorbate 80, wherein the single polyoxyethylenesorbitan fatty acid ester, e.g., polysorbate 80, is present in an amountrepresenting ˜0.05% w/v-˜5% w/v, ˜0.1% w/v-˜4% w/v, ˜0.15% w/v-˜3% w/v,˜0.2% w/v-˜2% w/v, or ˜0.2% w/v-˜1% w/v, such as for example about 0.25%w/v-2.5% w/v of the composition, e.g., about 1% w/v of the composition.In certain aspects, the single ingredient is TPGS, and TPGS is presentin an amount representing ˜0.05% w/v-˜5% w/v, ˜0.1% w/v-˜4% w/v, ˜0.15%w/v-˜3% w/v, ˜0.2% w/v-˜2% w/v, or ˜0.2% w/v-˜1% w/v, such as forexample about 0.25% w/v-2.5% w/v of the composition, e.g., about 1% w/vof the composition. In certain aspects, the single ingredient is apolyethoxylated castor oil, e.g., cremophor EL, wherein thepolyethoxylated castor oil, e.g., cremophor EL, is present in an amountrepresenting ˜0.05% w/v-˜5% w/v, ˜0.1% w/v-˜4% w/v, ˜0.15% w/v-˜3% w/v,˜0.2% w/v-˜2% w/v, or ˜0.2% w/v-˜1% w/v, such as for example about 0.25%w/v-2.5% w/v of the composition, e.g., about 1% w/v of the composition,wherein the cremophor provides both detectable or significantsolubilization and penetration enhancement activity. In aspects,compositions can comprise both a polyethoxylated castor oil, e.g., acremophor, and a polyoxyethylene sorbitan fatty acid ester, e.g.,polysorbate 80, wherein a combination solubilization/penetrationenhancer component comprises the two compounds in an amount representingabout 0.1% w/v to about 2% w/v of the composition, such as, e.g., about0.5% w/v to about 1.5% w/v, e.g., about 1% w/v, ˜1.5% w/v, or, e.g., ˜2%w/v of the composition. In aspects, such a composition can furthercomprise one or more constituents which provide detectable orsignificant penetration enhancement activity (e.g., a penetrationenhancing agent) or detectable or significant solubilization activity(e.g., a solubilization agent).

In aspects, the single constituent of the solubilization component ispolysorbate 80. In aspects, the single ingredient, e.g., the singlepolyoxyethylene sorbitan fatty acid ester, e.g., polysorbate 80, furtherprovides detectable or significant demulcent effect.

Demulcent Component (Demulcent(s))

In aspects, compositions provided by the invention comprise a demulcentcomponent. In aspects, the demulcent component comprises any one or morepharmaceutically acceptable and ophthalmologically suitable constituents(e.g., pharmaceutically acceptable and ophthalmologically suitablecompounds) which detectably or significantly increase the soothingeffect of the composition; detectably or significantly reduce the degreeof, or prevent, irritation caused by the composition or caused by one ormore other constituents of the composition; detectably or significantlyreduce the degree of, or prevent, inflammation caused by the compositionor caused by one or more other constituents of the composition; or acombination thereof. In aspects, the demulcent component can compriseany one or more pharmaceutically acceptable or ophthalmologicallysuitable compounds capable of demonstrating such an effect.

In aspects, one or more constituents of the demulcent component canfurther provide one or more additional detectable or significantfunctionalities, such as, for example, detectable or significantpenetration enhancement effect, detectable or significant solubilizationeffect, detectable or significant viscosity enhancing effect/thickeningeffect, or a combination thereof (such as is described for each sucheffect elsewhere herein). That is, in one aspect, a demulcentconstituent of the demulcent component also provides detectable orsignificant penetration enhancement effect. In one aspect, a demulcentconstituent of the demulcent component also provides detectable orsignificant solubilization effect. In one aspect, a demulcentconstituent of the demulcent component also provides detectable orsignificant viscosity enhancing/thickening effect. In one aspect, ademulcent constituent of the demulcent component also provides bothdetectable or significant penetration enhancement effect and detectableor significant solubilization effect. In one aspect, a demulcentconstituent of the demulcent component also provides detectable orsignificant viscosity enhancing/thickening effect. In certain aspects, ademulcent constituent of the demulcent component does not provide apenetration enhancement effect, a solubilization effect, or a viscosityenhancing/thickening effect. That is, in aspects, a penetration enhancerand a demulcent, a solubilizer and a demulcent, or, e.g., a demulcentand a thickening agent can be differing compounds.

In aspects, a demulcent component of a composition can comprise anyophthalmologically suitable and pharmaceutically acceptable demulcentwhich does not detectably or significantly interfere with the requiredfunctionality of any one or more other composition constituents, suchas, e.g., a PAC constituent, a BBC constituent, or both constituents ofthe PAC and the BBC. In aspects, exemplary constituents of a demulcentcomponent comprise, e.g., a constituent that also provides detectable orsignificant penetration enhancement activity, solubilization activity,or both penetration enhancement activity and solubilization activity,such as, e.g., polysorbate 80. In some aspects the polyoxyethylenesorbitan fatty acid ester can be a polyoxyethylene sorbitanoleate/polyoxyethylene sorbitan mono-oleate ester (e.g., polysorbate80). In some aspects, exemplary constituents of a demulcent componentcomprise, e.g., one or more polyols (sugar-like hydrogenatedcarbohydrates; sometimes referred to as polyhydric alcohols), e.g.,polyols in liquid form, such as for example glycerin, polyethyleneglycol 300, polyethylene glycol 400, polysorbate 80 as describedpreviously, propylene glycol, etc.

In aspects, exemplary constituents of a demulcent component comprise,e.g., one or more of pharmaceutically acceptable and ophthalmologicallysuitable cellulose derivatives, such as, e.g., carboxymethylcellulosesodium, hydroxyethyl cellulose, hypromellose, methylcellulose, etc.

In alternative aspects, an exemplary constituent of a demulcentcomponent is, e.g., a high-molecular-weight polysaccharide, e.g.,dextran 70. In still further aspects, an exemplary constituent of ademulcent component is, e.g., gelatin. In yet further aspects, anexemplary constituent of a demulcent component is, e.g., polyvinylalcohol (PVA). In some aspects, an exemplary constituent of a demulcentcomponent is, e.g., povidone.

In aspects, compositions provided by the invention comprise a demulcentcomponent comprising one or more demulcent constituents, wherein thedemulcent component is present in the composition in a concentrationrepresenting about 0.01% w/v to about 5%, about 0.05% w/v to about 5%w/v, or another detectably, physiologically effective, or significantamount of the composition, such as, e.g., ˜0.1% w/v-˜5% w/v, ˜0.15%w/v-˜5% w/v, ˜0.2% w/v-˜5% w/v, or ˜0.25% w/v-˜5% w/v, such as ˜0.05%w/v-˜5% w/v, ˜0.05% w/v-˜4.5% w/v, ˜0.05% w/v-˜4% w/v, ˜0.05% w/v-˜3.5%w/v, ˜0.05% w/v-˜3% w/v, ˜0.05% w/v-˜2.5% w/v, ˜0.05% w/v-˜2% w/v,˜0.05% w/v-˜1.5% w/v, or ˜0.05% w/v-˜1% w/v, such as ˜0.1% w/v-˜4% w/v,˜0.15% w/v-˜3% w/v, ˜0.2% w/v-˜2% w/v, ˜0.2% w/v-˜1% w/v, or ˜0.2%w/v-˜0.5% w/v, such as for example about 0.25% w/v, about 0.5% w/v, or,e.g., about 1% w/v of the composition.

In certain aspects, the demulcent component comprises two or moreconstituents wherein the total concentration/amount of the two or moredemulcent component constituents is represented by theconcentrations/amounts provided above. In aspects, the demulcentcomponent comprises a single constituent wherein the single constituentis present in an amount represented by the concentrations/amountsprovided above. In certain aspects, the demulcent component comprisestwo or more of polyoxyethylene sorbitan fatty acid esters wherein thetotal amount of the two or more polyoxyethylene sorbitan fatty acidesters is represented by the concentrations/amounts provided above. Inaspects, the demulcent component comprises a single polyoxyethylenesorbitan fatty acid ester, wherein the total amount of the singlepolyoxyethylene sorbitan fatty acid ester is represented by theconcentrations/amounts provided above. In certain aspects, the demulcentcomponent comprises a single constituent, the single constituent being apolyoxyethylene sorbitan fatty acid ester, such as, e.g., polysorbate80, wherein the single polyoxyethylene sorbitan fatty acid ester, e.g.,polysorbate 80, is present in an amount representing ˜0.05% w/v-˜5% w/v,˜0.1% w/v-˜4% w/v, ˜0.15% w/v-˜3% w/v, ˜0.2% w/v-˜2% w/v, ˜0.2% w/v-˜1%w/v, or ˜0.2% w/v-˜0.5% w/v, such as for example about 0.25% w/v, about0.5% w/v, or, e.g., about 1% w/v of the composition. In aspects, thesingle constituent of the demulcent component is polysorbate 80.

In certain alternative aspects, compositions comprise a demulcentcomponent wherein the demulcent component comprises a cellulosederivative in an amount of about 0.2% w/v-about 2.5% w/v of thecomposition, typically in an amount of less than or equal to about 1%w/v. In aspects, compositions comprise a demulcent component wherein thedemulcent component comprises dextran 70 in an amount of about 0.1% w/vof the composition. In aspects, a demulcent component comprising dextran70 further comprises one or more additional demulcent constituents. Inaspects, compositions comprise a demulcent component wherein thedemulcent component comprises gelatin in an amount of about 0.01% w/v ofthe composition. In aspects, compositions comprise a demulcent componentwherein the demulcent component comprises polyvinyl alcohol (PVA) in anamount of about 0.1% w/v-about 4% w/v of the composition. In aspects,compositions comprise a demulcent component wherein the demulcentcomponent comprises povidone in an amount of about 0.1% w/v-about 2% w/vof the composition.

In certain aspects, compositions comprise a demulcent componentrepresenting about 0.01% w/v-about 2% w/v, such as, e.g., about 1%w/v-about 3% w/v, or, e.g., about 2% w/v-about 5% w/v. In aspects,treatment of an ophthalmic condition/ocular condition with compositionsprovided by the invention comprising a demulcent component, e.g.,comprising polysorbate-80 or one or more other demulcents of a demulcentcomponent, detectably or significantly reduce or prevent inflammation,irritation, or both, over (as compared to) similar compositions(compositions comprising about the same or the same amount of most,generally all, substantially all, or all of the otherwise sameingredients), not comprising a demulcent. In aspects, such amount(s)disclosed here of a demulcent component is advantageous in that itprovides a detectable or significant demulcent effect compared toessentially the same, generally the same, or the same composition(s)lacking such a demulcent component, making use, e.g., repeated use orprolonged use (e.g., use for a sufficient period of time so as to resultin a detectable or significant clinical effect on the target indication,such as, e.g., elevated intraocular pressure, glaucoma, or both)tolerable to the user. In aspects, such amount(s) of a demulcent isadvantageous as such amounts can in aspects be provided without causingdetectable or significant interference with any one or more othercomponents. In aspects, a demulcent component can bolster the effect ofone or more other components (e.g., by further providing a detectable orsignificant contribution to the solubility of one or more constituentsof the composition (e.g., one or more constituents of a PAC, BBC, orboth) or by enhancing the penetration into ocular tissue of one or moreconstituents of the composition (e.g., amount of the constituentpenetrating ocular tissue, rate of constituent penetrating oculartissue, or both). Thus, in aspects, such amount(s) of a demulcentcomponent is/are advantageous in that the demulcent component candetectably or significantly contribute to the efficacy, stability, orboth efficacy and stability of compositions comprising such a demulcentcomponent.

In aspects, such amounts of a demulcent component, demulcent componentconstituents, or both, disclosed in this section represent an effectiveamount of a demulcent component, demulcent component constituent, orboth. According to certain aspects, composition(s) provided herein lackany constituent demonstrating detectable or significant demulcentactivity(ies).

In this and any other ingredient aspect of the invention, the inventionalso can be characterized as comprising a “means” for providing arecited function, here imparting/providing an effective, detectable, orsignificant demulcent effect (e.g., soothing, or reduced irritationeffect) to one or more constituents of composition(s) of the invention.In such a respect, any known equivalents of such named agents can alsobe, e.g., are, incorporated into compositions or methods of theinvention. As with other sections similarly described herein, any of thecomponents of the invention can be, where suitable, described as means(e.g., the above-described demulcent agents/compounds or components canbe described as demulcent means or means for providing effective,detectable, or significant demulcent activity/characteristics to one ormore constituents of the composition.)

Buffer Component (Buffer(s))

In aspects, compositions provided by the invention comprise a buffercomponent. In aspects, the buffer component comprises any one or morepharmaceutically acceptable and ophthalmologically suitable constituents(e.g., pharmaceutically acceptable and ophthalmologically suitablecompounds) which provide detectable or significant pH buffering effect,such that, e.g., the compositions maintain a pH within the pH rangesdescribed herein for extended periods of time (e.g., a pH of about6-about 8, e.g., ˜6-˜7.8, ˜6-˜7.6, or ˜6-˜7.4, such as, e.g., ˜6.2-˜8,˜6.4-˜8, ˜6.6-˜8, ˜6.8-˜8, ˜7-˜8, ˜7.2-˜8, or ˜7.4-˜8, such as, e.g.,˜6.2-˜7.8, or, e.g., ˜7-˜7.5) when stored at about 25° C. +/−2° C. andabout 40% +/−5% relative humidity; about 40° C. +/−2° C. and not morethan about 25% relative humidity; about 15° C.-about 27° C. and about60% relative humidity; about 38° C.-about 42° C. and 75% relativehumidity; or when stored under any such condition, or a sequentialcombination of such conditions, for a period of at least about 1 month,e.g., ≥˜3, ≥˜6, ≥˜9, ≥˜12, ≥˜18, ≥˜24, or, e.g., at least about 36months.

According to some aspects, compositions described herein do not comprisea buffer component. In aspects, compositions provided by the inventiondo not comprise any constituent characterizable as a buffer.

In aspects, compositions described herein can comprise one or morebuffers or pH-adjusting agents (such agents described in more detailelsewhere herein) used to adjust or maintain the pH within a target pHrange, such as, e.g., from about 6 to about 8, e.g., ˜6.2-˜7.8 or˜7-˜7.5. In aspects, one or more constituents of the buffer componentcan further provide one or more additional detectable or significantfunctionalities, such as, for example, detectable or significant pHadjusting effects. In some aspects, a constituent of a buffer componentcan contribute the tonicity of the composition. In aspects, a buffercomponent can be selected (or characterized by), at least in part, toaid in or adding in (detectably or significantly promoting) theestablishment of a target tonicity. Therefore, in some embodiments, oneor more buffers and one or more tonicity agents can combine tocontribute to the osmolality of a composition. In aspects, a buffercomponent can be selected or characterized by, at least in part, basedupon the presence of one or more other constituents of the compositionand, e.g., their concentration(s) (such as, e.g., contemplating thetonicity contribution of one or more other composition constituents).

In aspects, a buffer component of a composition can comprise anyophthalmologically suitable and pharmaceutically acceptable buffer whichdoes not detectably or significantly interfere with the requiredfunctionality of any one or more other composition constituents. Inaspects, exemplary constituents of a buffer component comprise, e.g.,one or more of a phosphate buffer (e.g., sodium phosphate, e.g.,monobasic or dibasic sodium phosphate), citrate buffer (e.g., sodiumcitrate compound, e.g., sodium citrate dihydrate), tris buffer,carbonate buffer (e.g., ammonium carbonate, sodium carbonate or sodiumbicarbonate), succinate buffer, maleate buffer, a borate buffer,combinations of sodium hydroxide, potassium hydroxide, hydrochloricacid, lactic acid, phosphoric acid, sulfuric acid, etc. or combinationsthereof. In specific aspects, compositions provided by the invention donot comprise a borate buffer, e.g., compositions do not comprise boricacid or sodium borate. Here, disclosures of aspects based on “notcomprising” an element provide simultaneous support for having very lowamounts of an element, lacking an effective amount of an element, orlacking any detectable amount of such an element, etc.

In aspects, compositions provided by the invention comprise a buffercomponent comprising one or more buffering agents, wherein the buffercomponent is present in the composition in a concentration representingabout 0.005% w/v to about 1.5% w/v of the composition, such as, e.g.,˜0.01% w/v-˜0.5% w/v, ˜0.015% w/v-˜0.5% w/v, or ˜0.02% w/v-˜0.5% w/v,e.g., ˜0.01% w/v-˜0.4% w/v, ˜0.01% w/v-˜0.3% w/v, ˜0.01% w/v-˜0.2% w/v,˜0.01% w/v-˜0.1% w/v, or ˜0.01% w/v-˜0.05% w/v of the composition.

In aspects, compositions provided by the invention comprise a buffercomponent comprising one or more buffering agents, wherein the buffercomponent is present in the composition in a concentration representingabout 0.01% w/v to about 1.5% w/v of the composition, such as, e.g.,˜0.05% w/v-˜1.5% w/v, ˜0.1% w/v-˜1.5% w/v, ˜0.2% w/v-˜1.5% w/v, ˜0.3%w/v-˜1.5% w/v, ˜0.4% w/v-˜1.5% w/v, or ˜0.5% w/v-˜1.5% w/v of thecomposition.

In aspects, compositions provided by the invention comprise a buffercomponent comprising one or more buffering agents, wherein the buffercomponent is present in the composition in a concentration representingabout 0.05% w/v to about 1.5% w/v of the composition, such as, e.g.,˜0.06% w/v-˜1.2% w/v, ˜0.08% w/v-˜1% w/v, ˜0.1% w/v-˜0.8% w/v, ˜0.12%w/v-˜0.7% w/v, ˜0.14% w/v-˜0.6% w/v, ˜0.16% w/v-˜0.4% w/v, ˜0.18%w/v-˜0.3% w/v, or, e.g., ˜0.2% w/v-˜0.3% w/v.

In one exemplary aspect, compositions comprise a citrate buffer, e.g.,citric acid monohydrate, in an amount of ˜0.005% w/v-˜0.09%, e.g.,˜0.01% w/v-˜0.05% w/v, 0.01% w/v-˜0.04% w/v, 0.01% w/v-˜0.03% w/v, or0.01% w/v-˜0.02% w/v, such as about 0.014% w/v of the composition.

In another exemplary aspect, compositions comprise a phosphate buffer,e.g., dibasic sodium phosphate USP (heptahydrate) in an amount of ˜0.01%w/v-˜0.5% w/v of the composition, e.g., ˜0.02% w/v-˜0.5% w/v, ˜0.04%w/v-˜0.5% w/v, ˜0.06% w/v-˜0.5% w/v, ˜0.08% w/v-˜0.5% w/v, ˜0.1%w/v-˜0.5% w/v, ˜0.15% w/v-˜0.5% w/v, or ˜0.2% w/v-˜0.5% w/v, e.g. ˜0.01%w/v-˜0.45% w/v, ˜0.01% w/v-˜0.4% w/v, ˜0.01% w/v-˜0.35% w/v, or ˜0.01%w/v-˜0.3% w/v, such as ˜0.05% w/v-˜0.4% w/v, ˜0.1% w/v-˜0.35% w/v,˜0.15% w/v-˜0.3% w/v, or ˜0.3% w/v-˜0.3% w/v, such as, e.g., ˜0.268% w/vof the composition.

In aspects, compositions comprise a buffer component comprising two ormore buffer constituents. For example, in aspects, compositions comprisea citrate buffer, e.g., citric acid monohydrate, in an amount of ˜0.005%w/v-˜0.09% w/v, e.g., ˜0.01% w/v-˜0.05% w/v, 0.01% w/v-˜0.04% w/v,˜0.01% w/v-˜0.03% w/v, or ˜0.01% w/v-˜0.02% w/v, such as about 0.014%w/v of the composition, and a phosphate buffer, e.g., dibasic sodiumphosphate USP (heptahydrate) in an amount of ˜0.01% w/v-˜0.5% w/v of thecomposition, e.g., such as ˜0.05% w/v-˜0.4% w/v, ˜0.1% w/v-˜0.35% w/v,˜0.15% w/v-˜0.3% w/v, or ˜0.3% w/v-˜0.3% w/v, such as, e.g., ˜0.268% w/vof the composition.

In aspects, such amounts of a buffer component, buffer componentconstituents, or both, disclosed in this section represent an effectiveamount of a buffer component, buffer component constituent, or both.

In this and any other ingredient aspect of the invention, the inventionalso can be characterized as comprising a “means” for providing arecited function, here imparting/providing an effective, detectable, orsignificant pH buffering effect. In such a respect, any knownequivalents of such named agents can also be, e.g., are, incorporatedinto compositions or methods of the invention. As with other sectionssimilarly described herein, any of the components of the invention canbe, where suitable, described as means (e.g., the above-describedbuffering agents/compounds or components can be described as bufferingmeans/buffer means or means for providing effective, detectable, orsignificant pH buffering activity/characteristics to the composition.)

Tonicity Component (Tonicity Agent(s))

In aspects, compositions provided by the invention comprise a tonicitycomponent. In aspects, the tonicity component comprises any one or morepharmaceutically acceptable and ophthalmologically suitable constituents(e.g., pharmaceutically acceptable and ophthalmologically suitablecompounds) which detectably or significantly modify or aid in theestablishment of the tonicity of the composition. In aspects, thetonicity component can comprise any one or more pharmaceuticallyacceptable or ophthalmologically suitable compounds capable ofdemonstrating such an effect. In aspects, the tonicityagents/constituents of the tonicity component are suitable forestablishing compositions having a targeted isotonic range, e.g., anosmolality of about 171 mOsm/Kg-about 1711 mOsm/K, e.g., ˜200mOsm/Kg-˜1000 mOsm/K, ˜250 mOsm/Kg-˜500 mOsm/Kg, or, e.g., ˜280 mOsm/Kgto ˜370 mOsm/Kg.

In aspects, a tonicity component of a composition can comprise anyophthalmologically suitable and pharmaceutically acceptable tonicityagent which does not detectably or significantly interfere with therequired functionality of any one or more other compositionconstituents. In aspects, exemplary constituents of a tonicity componentcomprise, e.g., any one or more pharmaceutically acceptable andophthalmologically suitable tonicity agents including, e.g., sodiumchloride, potassium chloride, dextrose, glucose, glycerin, glycerol,mannitol, sorbitol, other electrolytes, etc. In certain aspects,compositions comprise a tonicity component wherein the tonicitycomponent does not comprise any constituent which may detectably orsignificantly promote microbial growth.

In aspects, compositions provided by the invention comprise a tonicitycomponent comprising one or more tonicity agents, wherein the tonicitycomponent is present in the composition in a concentration representingabout 0.005% w/v to about 1% w/v of the composition, such as, e.g.,˜0.005% w/v-˜0.95% w/v, ˜0.005% w/v-˜0.9% w/v, ˜0.005% w/v-˜0.85% w/v,or ˜0.005% w/v-˜0.8% w/v, such as, e.g., ˜0.05% w/v-˜1% w/v, ˜0.1%w/v-˜1% w/v, ˜0.2% w/v-˜1% w/v, ˜0.3% w/v-˜1% w/v, ˜0.4% w/v-˜1% w/v,˜0.5% w/v-˜1% w/v, ˜0.6% w/v-˜1% w/v, ˜0.7% w/v-˜1% w/v, or ˜0.8%w/v-˜1% w/v. In aspects, the tonicity component is present incompositions provided by the invention in an amount of about 0.5% w/vand about 1% w/v of the composition, such as in an amount of about 0.8%w/v.

In certain aspects, compositions provided by the invention comprise atonicity component comprising one or more tonicity agents, wherein thetonicity component is present in the composition in a concentrationrepresenting about 2% w/v to about 6% w/v of the composition, such as,e.g., ˜2.5% w/v-˜6% w/v, ˜3% w/v-˜6% w/v, ˜3.5% w/v-˜6% w/v, ˜4% w/v-˜6%w/v, or ˜4.5% w/v-˜6% w/v, e.g., ˜2% w/v-˜5.5% w/v, or ˜2% w/v-˜4.5%w/v, such as, e.g., ˜2.5% w/v-˜5.5% w/v, ˜3% w/v-˜5% w/v, ˜3.5% w/v-˜5%w/v, or ˜4% w/v-˜5% w/v, such as, e.g., ˜4.05% w/v.

In certain aspects, the tonicity component comprises two or moreconstituents wherein the total concentration/amount of the two or moretonicity component constituents is represented by any of the applicableconcentrations/amounts provided above or combinations thereof (e.g., asingle constituent present in an amount of about 0.005% w/v to about 1%w/v of the composition, and a single constituent present in an amount ofabout 2% w/v to about 6% w/v, for a total buffer component amountrepresenting about 1.005% w/v-about 7% w/v of the composition).

In aspects, the tonicity component comprises a single tonicityconstituent wherein the single constituent is present in an amountrepresented by the concentrations/amounts provided above. In certainaspects, the tonicity component comprises a single constituent, thesingle constituent being sodium chloride. In aspects, sodium chloride ispresent in an amount representing about 0.005% w/v to about 1% w/v ofthe composition, such as, e.g., ˜0.005% w/v-˜0.95% w/v, ˜0.005%w/v-˜0.9% w/v, ˜0.005% w/v-˜0.85% w/v, or ˜0.005% w/v-˜0.8% w/v, e.g.,˜0.006% w/v-˜0.84% w/v, ˜0.007% w/v-˜0.83% w/v, ˜0.008% w/v-˜0.82% w/v,˜0.009% w/v-˜0.81% w/v, such as, e.g., ˜0.01% w/v-˜0.8% w/v, or, e.g.,˜0.05% w/v-˜1% w/v, ˜0.1% w/v-˜1% w/v, ˜0.2% w/v-˜1% w/v, ˜0.3% w/v-˜1%w/v, ˜0.4% w/v-˜1% w/v, ˜0.5% w/v-˜1% w/v, ˜0.6% w/v-˜1% w/v, ˜0.7%w/v-˜1% w/v, or ˜0.8% w/v-˜1% w/v of the composition, such as, e.g., inan amount of about 0.8% w/v of the composition. In certain aspects, thetonicity component comprises a single constituent, the singleconstituent being mannitol, wherein the mannitol is present in an amountrepresenting about 2% w/v to about 6% w/v, e.g., ˜2.5% w/v-˜5.5% w/v,˜3% w/v-˜5% w/v, or ˜3.5% w/v-˜5% w/v, e.g., ˜4% w/v-˜5% w/v such asabout 4.5% w/v.

Any aspect described herein as comprising a single element of acomposition are to be understood as implicitly simultaneously disclosingcompositions that consist essentially of such an element, at least inrespect of any applicable component/function. Thus, for example, thepreceding paragraph implicitly discloses a composition that comprising atonicity constituent that consists essentially of sodium chloride (and,thus, can include other elements that do not materially modify, e.g.,detract from or impair, the novel characteristics of the element, heresodium chloride, in the provided context).

In some aspects, compositions provided by the invention comprise no morethan about 0.1% w/v of a tonicity agent. In some aspects, compositionsprovided by the invention comprise no more than about 0.1% w/v sodiumchloride. In some aspects, compositions provided by the inventioncomprise no more than about 4.1% w/v of a tonicity agent. In someaspects, compositions provided by the invention comprise no more thanabout 4.05% w/v mannitol.

In aspects, such amounts of a tonicity component, tonicity componentconstituents, or both, disclosed in this section represent an effectiveamount of a tonicity component, tonicity component constituent, or both.In certain aspects, composition(s) provided herein lack any constituentproviding detectable or significant tonicity-modifying activity(ies).

In this and any other ingredient aspect of the invention, the inventionalso can be characterized as comprising a “means” for providing arecited function, here imparting/providing an effective, detectable, ortonicity effect (e.g., establishment of a target osmolality orosmolality range). In such a respect, any known equivalents of suchnamed agents can also be, e.g., are, incorporated into compositions ormethods of the invention. As with other sections similarly describedherein, any of the components of the invention can be, where suitable,described as means (e.g., the above-described tonicity agents/compoundsor components can be described as tonicity means or means for providingeffective, detectable, or tonicity characteristics to the composition.)

Viscosity Enhancer Component (Viscosity Enhancing Agent(s), ThickeningAgent(s), Gelling Agent(s))

In aspects, compositions provided by the invention comprise a viscosityenhancer component (also referred to as a thickening component orgelling/gel component). In aspects, certain constituents of such acomponent may provide viscosity enhancement without forming a gel. Inaspects, as is described herein, a viscosity enhancer componentcomprises a constituent which only increases the viscosity of thecomposition after administration, e.g., after exposure to an environmentassociated with administration to a mammalian eye.

Herein, in aspects, constituents of the composition which impart aviscosity enhancing effect, e.g., an increase in viscosity compared tothe same composition without the constituent, or, e.g., an increase inviscosity after administration to a mammalian eye compared to thecomposition prior to administration to the mammalian eye, can be aconstituent of the viscosity enhancer component. In aspects, theviscosity enhancer component comprises any one or more pharmaceuticallyacceptable and ophthalmologically suitable constituents (e.g.,pharmaceutically acceptable and ophthalmologically suitable compounds)which detectably or significantly increase the viscosity, thickness, orgelling characteristics of the composition or of one or more otherconstituents of the composition. In certain aspects, one or moreconstituents of a viscosity enhancing component change from undercertain conditions so as to modify the viscosity of the composition(such as, e.g., a gel forming agent of a composition). In a specificexample, one or more constituents of a viscosity enhancing componentgels when the ionic environment changes (e.g., increases) (e.g., theionic environment is sufficiently increased), such that, e.g., thecomposition comprising the constituent is liquid when packaged, prior toadministration (e.g., when in its final packaging), however whenadministered to/delivered to a mammalian eye, the composition thickens,e.g., gels. In certain aspects, the invention provides composition(s)specifically characterizable as a gel. In some aspects, compositionscomprising a thickening component are gel compositions.

In aspects, one or more constituents of a thickening component canmodify the viscosity of the composition after administration, such as,e.g., it/they do not detectably or significantly increase the viscosityof the composition prior to administration compared to an at leastsubstantially similar composition lacking such constituent(s), but uponadministration to a mammalian eye cause the detectable or significantincrease in viscosity of the composition. In aspects, events uponadministration which can cause a thickening agent constituent toincrease the viscosity of the composition can be or include, e.g., (1)exposure to the environment of a mammalian eye to which the compositionmay be administered (or an environment, such as a test solution/media,that is substantially similar or the same in some, most, generally all,or all material respects), (2) exposure to an environment of at leastabout 28 degrees Celsius (° C.), such as the temperature of a mammalianeye to which it is administered, such as ≥˜29° C. or ≥˜30° C., e.g.,≥˜31° C., ≥˜32° C., ≥˜33° C., ≥˜34° C., or ≥˜35° C., (3) exposure to anenvironment having an ionic strength that is detectably or significantlygreater than that of one or more gelling agents present in thecomposition (e.g., gellan gum, or, e.g., guar gum); (4) exposure to anenvironment having a pH of greater than, about 6.2, e.g., ≥˜6.4, ≥˜6.6,≥˜6.8, ≥˜7, or, e.g., ≥˜7.2, or, e.g., combinations of any of (1)-(4).In aspects, upon exposure to such exemplified environments, aconstituent can aid in or cause the formation of a viscoelastic gel. Inaspects, the formation of such a gel in-situ (1) detectably orsignificantly increases the residence time of the APIs of thecomposition, (2) detectably or significantly enhances thebioavailability of the APIs of the composition, (3) detectably orsignificantly reduces the frequency of required dosing to achieve an atleast generally equivalent, substantially equivalent, effectivelyequivalent, or equivalent efficacy in treatment of the target condition,(4) improves patient compliance with administration regimen(s), or (5)any combination thereof, compared to an at least generally equivalent,at least substantially equivalent, at least effectively equivalent, orequivalent composition lacking such a gelation in-situ.

According to certain aspects, the invention provides compositionscomprising a viscosity enhancer component, wherein at least oneconstituent of the viscosity enhancer component is a gelling agent,wherein the gelling agent detectably or significantly increases theviscosity of the composition upon administration to the mammalian eyeover the viscosity of the composition immediately prior to theadministration of the composition to the mammalian eye within no morethan about 20 seconds of making contact with the mammalian eye, such as,e.g., within ≤˜18 seconds, ≤˜16 seconds, ≤˜14 seconds, ≤˜12 seconds,≤˜10 seconds, ≤˜8 seconds, ≤˜6 seconds, ≤˜4 seconds, or, ≤˜2 seconds,such as within ≤˜1 second of making contact with the mammalian eye.

In aspects, constituent(s) of a viscosity enhancer component detectablyor significantly improve the form of the formulation for convenientadministration (e.g., make the composition easier for a user to apply).In aspects, constituent(s) of a viscosity enhancer component detectablyor significantly improve, e.g., increase, contact of the compositionwith eye tissue, or e.g., detectably or significantly increase thelength of time the composition maintains contact with eye tissuefollowing administration. In aspects, constituent(s) of a viscosityenhancer component detectably or significantly improves (e.g.,detectably or significantly increases) bioavailability of activepharmaceutical ingredient(s) of the composition, such as, e.g.,constituents of the PAC, such as a bimatoprost compound, e.g.,bimatoprost base, constituents of the BBC, such as a timolol compound,e.g., a salt of timolol, e.g., timolol maleate, or, e.g., constituentsof both the PAC and BBC. In aspects, one or more constituents of theviscosity enhancer component can further provide one or more additionaldetectable or significant functionalities, such as, e.g., a detectableor significant demulcent effect.

In aspects, the viscosity enhancer component can comprise any one ormore pharmaceutically acceptable or ophthalmologically suitablecompounds capable of demonstrating such effect(s). In aspects, aviscosity enhancer component of a composition can comprise anyophthalmologically suitable and pharmaceutically acceptable viscosityenhancing agent which does not detectably or significantly interferewith the required functionality of any one or more other compositionconstituents.

In aspects, exemplary constituents of a viscosity enhancer componentcomprise, e.g., polymers containing, mostly composed, generallyconsisting of, or consisting of, hydrophilic groups such asmonosaccharides and polysaccharides, ethylene oxide groups, hydroxylgroups, carboxylic acids, or other charged functional groups.

In aspects, exemplary polymer constituents of a viscosity enhancercomponent are high molecular weight polymers, e.g., polymers having amolecular weight of at least about 15,000 Daltons (“Da”), such as, e.g.,≥˜20,000 Da, ≥˜30,000 Da, ≥˜40,000 Da, or, e.g., ≥˜50,000 Da, e.g.,about 15,000 Da to about 50,000 Da.

In aspects, exemplary polymer constituents of a viscosity enhancercomponent have a molecular weight of at least about 50,000 Da, such as,e.g., ≥˜60,000 Da, ≥˜70,000 Da, ≥˜80,000 Da, ≥˜90,000 Da, or, e.g.,≥˜100,000 Da, such as, e.g., ˜50,000 Da to ˜100,000 Da.

In aspects, exemplary polymer constituents of a viscosity enhancercomponent have a molecular weight of at least about 100,000 Da, such as,e.g., ≥˜110,000 Da, ≥˜120,000 Da, ≥˜130,000 Da, ≥˜140,000 Da, ≥˜150,000Da, ≥˜160,000 Da, ≥˜170,000 Da, ≥˜180,000 Da, ≥˜190,000 Da or, e.g.,≥˜200,000 Da, such as, e.g., ˜100,000 Da to ˜200,000 Da.

In aspects, exemplary polymer constituents of a viscosity enhancercomponent have a molecular weight of at least about 200,000 Da, such as,e.g., ≥˜210,000 Da, ≥˜220,000 Da, ≥˜230,000 Da, ≥˜240,000 Da, ≥˜250,000Da, ≥˜260,000 Da, ≥˜270,000 Da, ≥˜280,000 Da, ≥˜290,000 Da, or ≥˜300,000Da, such as, e.g., ˜200,000 Da-˜300,000 Da.

In aspects, exemplary polymer constituents of a viscosity enhancercomponent have a molecular weight of at least about 300,000 Da, such as,e.g., ≥˜310,000 Da, ≥˜320,000 Da, ≥˜330,000 Da, ≥˜340,000 Da, ≥˜350,000Da, ≥˜360,000 Da, ≥˜370,000 Da, ≥˜380,000 Da, ≥˜390,000 Da, or, e.g.,≥˜400,000 Da, such as, e.g., ˜300,000 Da-˜400,000 Da.

In aspects, exemplary polymer constituents of a viscosity enhancercomponent have a molecular weight of at least about 400,000 Da, such as,e.g., ≥˜410,000 Da, ≥˜420,000 Da, ≥˜430,000 Da, ≥˜440,000 Da, ≥˜450,000Da, ≥˜460,000 Da, ≥˜470,000 Da, ≥˜480,000 Da, ≥˜490,000 Da, or ≥˜500,000Da, such as, e.g., ˜410,000 Da-˜500,000 Da.

In certain aspects, exemplary polymer constituents of a viscosityenhancer component have a molecular weight of at least about 500,000 Da,such as ˜500,000 Da-˜1,500,000 Da, e.g., 500,000 Da-˜1,250,000 Da,500,000 Da-˜1,000,000 Da, or 500,000 Da-˜750,000 Da, e.g., 750,000Da-˜1,500,000 Da, 1,000,000 Da-˜1,500,000 Da, or 1,250,000 Da-˜1,500,000Da. In certain aspects, exemplary polymer constituents of a viscosityenhancer component have a molecular weight of greater than 1,500,000 Da.

In certain aspects, exemplary polymer constituents of a viscosityenhancer component provide a detectable or significant increase inviscosity compared to the composition without the constituent(s), suchas, e.g., an increase in viscosity over the composition without theconstituent(s) either (1), while packaged, prior to use, (2) afteradministration to a mammalian eye (e.g., upon being placed underdetectably or significantly different tonicity conditions), or (3) both(1) and (2), of at least about 0.5%, ≥˜1%, ≥˜3%, ≥˜5%, ≥˜10%, ≥˜15%,≥˜20%, ≥˜25%, ≥˜30%, ≥˜35%, ≥˜40%, ≥˜45%, or, e.g., ≥˜50%.

In aspects, examples of suitable viscosity-enhancing agents include,e.g., sodium carboxymethylcellulose, hydroxypropylmethylcellulose,povidone, polyvinyl alcohol, polyethylene glycol, and gellan gum. Incertain aspects, examples of suitable viscosity-enhancing agentsinclude, e.g., agents capable of forming a gel in-situ, such as, e.g., apolymer such as a triblock copolymer poly (ethylene oxide)-b-poly(propylene oxide)-b-poly (ethylene oxide) (PEO-PPO-PEO) (e.g., pluronicsor poloxamers), such as, e.g., the poloxamers 188 (F-68), 237 (F-87),338 (F-108) and 407 (F-127), Pluronic F-127 (F-127) or Poloxamer 407(P407) (copolymer PEO106-PPO70-PEO106); gellan gum, guar gum, xanthangum, chitosan, xyloglucan (often referred to as tamarind seedpolysaccharide (TSP), polyacrylic acid polymers (e.g., Carbopol),alginate (alginic acid), e.g., calcium alginate, sodium alginate, etc.,pectin, carrageenan, cellulose derivatives such as, e.g., methylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC),sodium carboxymethyl cellulose (NaCMC), etc. In aspects, combinations ofsuch agents can provide gelation activity, such as, e.g., a Carbopol andHPMC, or a Carbopol and chitosan, or, e.g., calcium alginate and HPMC,gellan gum with xanthan gum, HPMC, or Carbopol, gellan gum andcarrageenan, etc. In aspects, a single agent can be present, such as,e.g., guar gum or, e.g., gellan gum. In one aspect, compositions arefree of carbomer type gelling agent.

In certain aspects, formulations described herein lack any viscosityenhancer component, e.g., lack any thickening (e.g.,viscosity-enhancing) compounds or agents/constituents.

In aspects, compositions provided by the invention comprise a viscosityenhancer component comprising one or more viscosity enhancing agents,wherein the viscosity enhancer component is present in the compositionin a concentration representing about 0.1% w/v to about 1% w/v of thecomposition, such as, e.g., ˜0.1% w/v-˜0.9% w/v, ˜0.1% w/v-˜0.8% w/v,˜0.1% w/v-˜0.7% w/v, or ˜0.1% w/v-˜0.6% w/v, e.g., ˜0.2% w/v-˜1% w/v,˜0.3% w/v-˜1% w/v, ˜0.4% w/v-˜1% w/v, ˜0.5% w/v-˜1% w/v, or ˜0.6%w/v-˜1% w/v, such as, e.g., ˜0.2% w/v-˜9% w/v, ˜0.3% w/v-˜0.8% w/v,˜0.4% w/v-˜0.7% w/v, ˜0.5% w/v-˜0.7% w/v, or, e.g., about 0.6% w/v ofthe composition.

In certain aspects, the thickening component comprises two or moreconstituents wherein the total concentration/amount of the two or morethickening component constituents is represented by theconcentrations/amounts provided above. In aspects, the solubilizationcomponent comprises a single constituent wherein the single constituentis present in an amount represented by the concentrations/amountsprovided above. In certain aspects, the solubilization componentcomprises a single constituent, the single constituent being gellan gum,wherein the gellan gum, is present in an amount representing ˜0.2%w/v-˜9% w/v, ˜0.3% w/v-˜0.8% w/v, ˜0.4% w/v-˜0.7% w/v, ˜0.5% w/v-˜0.7%w/v, or, e.g., about 0.6% w/v of the composition.

In aspects, such amounts of a viscosity enhancer component, viscosityenhancer component constituents, or both, disclosed in this sectionrepresent an effective amount of a viscosity enhancer component,viscosity enhancer component constituent, or both.

In this and any other ingredient aspect of the invention, the inventionalso can be characterized as comprising a “means” for providing arecited function, here imparting/providing an effective, detectable, orsignificant viscosity enhancing, thickening, or gelling effect tocomposition(s) of the invention. In such a respect, any knownequivalents of such named agents can also be, e.g., are, incorporatedinto compositions or methods of the invention. As with other sectionssimilarly described herein, any of the components of the invention canbe, where suitable, described as means (e.g., the above-describedviscosity enhancing agents/compounds or components can be described asviscosity enhancing, thickening, or gelling means or means for providingeffective, detectable, or significant viscosity enhancing, thickening,or gelling activity/characteristics to the composition.)

Chelation Component (Chelating Agent(s))

In aspects, compositions provided by the invention comprise a chelationcomponent. In aspects, the chelation component comprises any one or morepharmaceutically acceptable and ophthalmologically suitable constituents(e.g., pharmaceutically acceptable and ophthalmologically suitablecompounds) which detectably or significantly increase chelation withinthe composition, detectably or significantly supplement or enhancepreservative efficacy, or a combination thereof, by forming stablewater-soluble complexes (chelates) with alkaline earth and heavy metalions, by sequestering divalent or polyvalent metal cations, or both. Inaspects, constituent(s) of a chelation component remain effective at apH of between about 6.5 and 8.0. In aspects, the chelation component cancomprise any one or more pharmaceutically acceptable orophthalmologically suitable compounds capable of demonstrating such aneffect. In aspects, a chelation component of a composition can compriseany ophthalmologically suitable and pharmaceutically acceptablechelating agent which does not detectably or significantly interferewith the required functionality of any one or more other compositionconstituents. In certain aspects, compositions provided herein do notcomprise compound(s) providing detectable or significant chelatingactivity(ies).

In aspects, exemplary constituents of a chelation component comprise,e.g., one or more of cromolyn, monomeric polyacids such as EDTA,cyclohexanediamine tetraacetic acid (CDTA), hydroxyethylethylenediaminetriacetic acid (HEDTA), diethylenetriamine pentaacetic acid (DTP A),dimercaptopropane sulfonic acid (DMPS), dimercaptosuccmic acid (DMSA),aminotrimethylene phosphonic acid (ATP A), citric acid, anyophthalmologically acceptable salts thereof, and/or combinations of anytwo or more such compounds. In other aspects, a chelating agent can be aphosphate, such as, e.g., pyrophosphates, tripolyphosphates, and,hexametaphosphates; a chelating antibiotic such as chloroquine andtetracycline; a nitrogen-containing chelating agent containing two ormore chelating nitrogen atoms within an imino group or in an aromaticring (e.g., diimines, 2,2′-bipyridines, etc.); or for example apolyamine such as cyclam (1,4,7,11-tetraazacyclotetradecane), N—(C₁-C₃₀alkyl)-substituted cyclams (e.g., hexadecyclam,tetramethylhexadecylcyclam), diethylenetriamine (DETA), spermine,diethylnorspermine (DENSPM), diethylhomospermine (DEHOP), anddeferoxamine (N′-[5-[[4-[[5-(acetylhydroxyamino)pentyl]amino]-1,4-dioxobutyl]hydroxy-amino]pentyl]-N′-(5-aminopentyl)-N-hydroxybutanediamide;also known as desferrioxamine B and DFO).

In certain aspects, a chelation component of compositions provided bythe invention comprise EDTA or an ophthalmologically suitable EDTA saltsuch as, e.g., diammonium EDTA, disodium EDTA, dipotassium EDTA,triammonium EDTA, trisodium EDTA, tripotassium EDTA, or calcium disodiumEDTA.

In aspects, compositions provided by the invention comprise a chelationcomponent comprising one or more chelating agents, wherein the chelationcomponent is present in the composition in a concentration representingabout 0.001% w/v-about 0.1% w/v, such as, e.g., about 0.002% w/v-0.1%w/v, about 0.004% w/v-about 0.1% w/v, about 0.006% w/v-about 0.1% w/v,about 0.008% w/v-about 0.1% w/v, or for example about 0.01% w/v-about0.1% w/v or, e.g., comprising another detectably, physiologicallyeffective, or significant amount.

In certain aspects, the chelation component comprises two or moreconstituents wherein the total concentration/amount of the two or morechelation component constituents is represented by, e.g., any of theapplicable concentrations/amounts provided above. In aspects, thechelation component comprises a single constituent wherein the singleconstituent is present in an amount represented by theconcentrations/amounts provided above, such as, e.g., edetate disodiumin amounts provided above.

In aspects, such amounts of a chelation component, chelation componentconstituents, or both, disclosed in this section represent an effectiveamount of a chelation component, chelation component constituent, orboth.

In this and any other ingredient aspect of the invention, the inventionalso can be characterized as comprising a “means” for providing arecited function, here imparting/providing an effective, detectable, orsignificant chelating effect (e.g., forming stable water-solublecomplexes (chelates) with alkaline earth and heavy metal ions) ofcompositions. In such a respect, any known equivalents of such namedagents can also be, e.g., are, incorporated into compositions or methodsof the invention. As with other sections similarly described herein, anyof the components of the invention can be, where suitable, described asmeans (e.g., the above-described chelating agents/compounds orcomponents can be described as chelation means or means for providingeffective, detectable, or significant chelation activity/characteristicsto the composition or one or more constituents of the composition.)

pH Adjusting Component (pH Adjusting Agent(s))

In aspects, compositions provided by the invention comprise a pHadjusting component. In aspects, the pH adjusting component comprisesany one or more pharmaceutically acceptable and ophthalmologicallysuitable constituents (e.g., pharmaceutically acceptable andophthalmologically suitable compounds) which detectably or significantlyalter or aid in the establishment of a target pH of the composition,such as a pH of between about 6 to about 8, such as a pH of about 6.2 toabout 7 or, e.g., a pH of about 6.9 to about 7.5. In aspects, the pHadjusting component can comprise any one or more pharmaceuticallyacceptable or ophthalmologically suitable compounds capable ofdemonstrating such an effect. In aspects, a pH adjusting component of acomposition can comprise any ophthalmologically suitable andpharmaceutically acceptable pH adjusting agent which does not detectablyor significantly interfere with the required functionality of any one ormore other composition constituents.

In aspects, one or more constituents of the pH adjusting component canfurther provide one or more additional detectable or significantfunctionalities, such as, for example, detectable or significantbuffering effects (as described elsewhere herein). In aspects, a pHadjusting agent of a composition can be a compound that is differentfrom a buffer/buffering agent of the composition. In some aspects, aconstituent of a pH adjusting component can contribute the tonicity ofthe composition. Therefore, in some embodiments, one or more pHadjusting component constituents and one or more tonicity agents cancombine to contribute to the osmolality of a composition.

In aspects, exemplary constituents of a buffer component comprise, e.g.,one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate,potassium hydroxide, ammonium carbonate, hydrochloric acid, lactic acid,phosphoric acid, sodium phosphate, sulfuric acid, etc. In aspects, suchagents can be used to adjust the pH to a desirable/target range, suchas, e.g., to about 6 to about 7.2, such as ˜6.1-˜7.1, ˜6.1-˜7, or˜6.2-˜7, or, e.g., to about 6.5 to about 8, such as ˜6.6-˜7.8,˜6.8-˜7.6, or ˜7-˜7.5, such as ˜71-˜7.3. In aspects, the pH of thecompositions, e.g., compositions comprising a bimatoprost compound,e.g., bimatoprost base, and a timolol compound, e.g., timolol maleate,can be adjusted in any suitable manner by means of the addition of pHadjusting agents in an amount sufficient to establish and maintain acomposition pH of, e.g., from about 6-about 7.5, such as, e.g., about6.2-about 7, or, e.g., about 6.9-about 8, e.g., ˜6.9-˜7.5, for exampleby addition of aqueous hydrochloric acid solutions or aqueous sodiumhydroxide solutions. Such pH adjusting solutions can be diluted orconcentrated in any suitable manner to achieve a desired effect/state.E.g., in aspects, suitable pH adjusting agents include 0.01 molar (M)hydrochloric acid (“HCl”), 0.1M HCl, 1M HCl, 2M HCl, 3M HCl, 4M HCl, 5MHCl, 6M HCl (e.g., a 0.01-6 M, such as 0.1-5 M, e.g., 0.25-5 M, or 0.2-4M HCl), 0.01M sodium hydroxide (“NaOH”), 0.1M NaOH, 1M NaOH, 2M NaOH, 3MNaOH, 4M NaOH, 5M NaOH (e.g., 0.01 M-5 5M NaOH, such as 0.2-5 M, 0.25-4M, or 0.3-6M or 0.3-3M NaOH), and 6M NaOH. In one aspect, suitable pHadjusting agents include either one of or a combination of HCl or NaOH,e.g., 1M HCl or 1M NaOH, which, in aspects, alternatively can be addedto a composition to achieve a desired pH range.

In aspects, compositions provided by the invention can comprise a pHadjusting component comprising one or more pH adjusting agent(s),wherein the pH adjusting component is present in the compositionsprovided by the invention in an amount effective in providing the targetpH. In aspects, such an amount can be considered a “trace amount,” e.g.,less than ˜0.005% w/v, <0.004% w/v, ≤˜0.003% w/v, <0.002% w/v, e.g.,≤˜0.001% w/v. In aspects, such an amount can be an amount representingabout 0-about 0.01% w/v. In aspects, one or more pH adjusting agent(s)can be present in the compositions provided by the invention in anamount effective in providing the target pH, such amounts representingabout 0% w/v-about 0.1% w/v, such as, e.g., about 0.01% w/v, ˜0.02% w/v,˜0.03% w/v, ˜0.04% w/v, ˜0.05% w/v, ˜0.06% w/v, ˜0.07% w/v, ˜0.08% w/v,or, e.g., ˜0.09% w/v.

In certain aspects, the pH adjusting component comprises two or moreconstituents wherein the total concentration/amount of the two or morepH adjusting component constituents within one or more ranges providedabove. In aspects, the pH adjusting component comprises a singleconstituent wherein the single constituent is present in an amountwithin one or more ranges provided above. In aspects, compositionscomprise NaOH, HCl, or both NaOH and HCl only in sufficient amounts toadjust pH during the manufacturing process (e.g., in an amount of lessthan 0.1% w/v, or, e.g., less than ˜0.005% w/v).

In aspects, such amounts of a pH adjusting component, pH adjustingcomponent constituents, or both, disclosed in this section represent aneffective amount of a pH adjusting component, pH adjusting componentconstituent, or both.

In this and any other ingredient aspect of the invention, the inventionalso can be characterized as comprising a “means” for providing arecited function, here imparting/providing an effective, detectable, orsignificant pH adjustment effect (e.g., pH establishment) to/ofcomposition(s) of the invention. In such a respect, any knownequivalents of such named agents can also be, e.g., are, incorporatedinto compositions or methods of the invention. As with other sectionssimilarly described herein, any of the components of the invention canbe, where suitable, described as means (e.g., the above-described pHadjusting agents/compounds or components can be described as pHadjusting means or means for providing effective, detectable, orsignificant pH adjustment activity/characteristics to the composition).In such aspects, it is understood that known equivalents to the recitedelements provided herein also can be utilized/present in the place ofsuch specifically named elements.

Antioxidant Component (Antioxidant(s))

In aspects, compositions comprise antioxidant(s) in effective amount(s).An “antioxidant” is typically understood as referring to a substancethat preferentially reacts with oxygen, thereby detectably orsignificantly protecting other components of a composition to which itis added from premature degradation due to oxidation (e.g., protectingAPIs that is known to be detectably/significantly susceptible tooxidation).

According to aspects, one or more antioxidant compounds can be presentin composition(s) of the invention as an antioxidant component, whichdetectably or significantly improve API stability or reduce the amountof impurities, such as, e.g., providing for a composition which isstable under room temperature storage conditions, e.g., retains at leastabout 97% of the one or more PAC constituents, e.g., bimatoprostcompound(s), retains at least about 97% of the one or more BBCconstituents, e.g., timolol compound(s), or retains at least about 97%of one or more PAC constituents and one or more BBC constituents whenstored at about 15° C.-about 27° C. and about 60% relative humidity,when stored at about 38° C.-about 42° C. and 75% relative humidity, orwhen stored under either condition or a sequential combination of suchconditions, for at least about one month such as ≥˜2 months or such as≥˜3 months, ≥˜6 months, ≥˜12 months, or, e.g., ≥˜18 months, ≥˜24 months,or ≥˜36 months.

For example, composition(s) provided by the invention can comprise anantioxidant component comprising one or more antioxidant agents whichdetectably improve the stability of the one or more bimatoprostcompound(s), one or more timolol compound(s), or both one or morebimatoprost compound(s) and one or more timolol compound(s), reduces theamount of composition impurities, enhances preservative effectiveness,or any or all thereof, at a period of at least 2 weeks postmanufacturing, such as at a period ≥˜3 weeks, ≥˜1 month, ≥˜6 weeks, ≥˜2months, ≥˜10 weeks, ≥˜3 months, ≥˜14 weeks, ≥˜4 months, ≥˜18 weeks, ≥˜5months, ≥˜22 weeks, ≥˜6 months, or for even longer periods (e.g., 3-24,3-18, 3-12, 3-36, 4-12, 4-24, 4-36, 6-12, 6-18, 6-24, or 6-36 months).

In aspects, the invention provides composition(s) comprising one or morepharmaceutically acceptable and ophthalmologically suitable antioxidantagents as constituents of an antioxidant component effective at pH rangeof, e.g., ˜6.2-˜7, or, e.g., ˜6.9-˜7.5. In aspects, antioxidantcompound(s) of the composition(s) herein do not detectably orsignificantly negatively impact any other component of the formulation,such as, e.g., they do not detectably or significantly reduce theefficacy of any one or more API(s), e.g., bimatoprost compound(s),timolol compound(s), or both.

In aspects any ophthalmologically suitable and pharmaceuticallyacceptable antioxidant can be used in methods of theinvention/incorporated in compositions of the invention, in any suitablyeffective amount(s). In aspects, exemplary antioxidant(s) in acomposition described herein can comprise, e.g., sodium ascorbate,ascorbic acid, thiamine, pyridoxine, histidine, cysteine, glutathione,sodium bisulphite, sodium sulphite, sodium metabisulphite, sodiumthiosulphite, sodium formaldehyde sulphoxylate, acetylcysteine,cysteine, thioglycerol, thioglycollic acid, thiolactic acid, thieurea,dihithreitol, propyl gallate, butylated hydroxyanisole, butylatedhydroxytoluene, tertiary butyl hydroquinone, ascorbyl palmitate,nordihydroguaiaretic acid and alpha-tocopherol, any ophthalmologicallyacceptable salts thereof, or combinations of any two or more suchcompounds. In aspects, one or more antioxidant compound(s)/agent(s) canbe present in the compositions provided by the invention in an amountrepresenting about 0.001% w/v-about 2% w/v of the composition, such as,e.g., ˜0.001% w/v-˜1.8% w/v, ˜0.001% w/v-˜1.6% w/v, ˜0.001% w/v-˜1.4%w/v, ˜0.001% w/v-˜1.2% w/v, ˜0.08% w/v-˜1% w/v, e.g., ˜0.05-˜1% w/v ofthe composition, or another detectably, physiologically effective, orsignificant amount.

In aspects, such amounts of an antioxidant component, antioxidantcomponent constituents, or both, disclosed in this section represent aneffective amount of an antioxidant component, antioxidant componentconstituent, or both. In certain aspects, composition(s) provided hereinlack any constituent providing detectable or significant antioxidantactivity(ies).

In this and any other ingredient aspect of the invention, the inventionalso can be characterized as comprising a “means” for providing arecited function, here imparting/providing an effective, detectable, orsignificant antioxidant effect to/of composition(s) of the invention. Insuch a respect, any known equivalents of such named agents can also be,e.g., are, incorporated into compositions or methods of the invention.As with other sections similarly described herein, any of the componentsof the invention can be, where suitable, described as means (e.g., theabove-described antioxidant agents/compounds or components can bedescribed as antioxidant means or means for providing effective,detectable, or significant antioxidant activity/characteristics to thecomposition.)

Carrier Component (Carrier Agent(s))

In aspects, compositions provided by the invention comprise a carriercomponent. In aspects, this component may be referenced as vehiclecomponent. In aspects, the carrier component comprises any one or morepharmaceutically acceptable and ophthalmologically suitable constituents(e.g., pharmaceutically acceptable and ophthalmologically suitablecarriers) which detectably or significantly maintain all constituents ofthe composition in deliverable form, such as in the form of a liquid,e.g., a solution, or, e.g., a gel. In aspects, the carrier component cancomprise any one or more pharmaceutically acceptable orophthalmologically suitable carriers capable of performing such afunction. In aspects, a carrier component of a composition can compriseany ophthalmologically suitable and pharmaceutically acceptable carrierwhich does not detectably or significantly interfere with the requiredfunctionality of any one or more other composition constituents.

In aspects, exemplary constituents of a carrier component comprise,e.g., one or more of a pharmaceutically acceptable andophthalmologically suitable lipid (e.g., establishing a lipidcarrier/vehicle), a gel (e.g., establishing a gel carrier/vehicle), anoil-based carrier (establishing an oil-based carrier/vehicle), a carrierin the form of an emulsion (establishing an emulsion carrier/vehicle),an emulsifier-containing carrier that forms an emulsion when mixed withother components, or, a carrier forming a solution carrier/vehicle,e.g., water to form an aqueous solution carrier/vehicle. In aspects, thecarrier is an aqueous carrier. In aspects, the carrier is mostly,generally only, essentially only, substantially only, or only composedof water, e.g., water for injection (WFI) (a sterile, solute-freepreparation of distilled water). In alternative aspects, otherophthalmologically suitable aqueous carriers which do not adverselyaffect the stability of the composition(s) may be used, such as, e.g.,deionized water.

In aspects, compositions provided by the invention comprise a carriercomponent comprising one or more carriers, wherein the carrier componentis present in a concentration representing at least about 60% w/v of thecomposition, such as, e.g., ≥˜65% w/v, ≥˜70% w/v, ≥˜75% w/v, ≥˜80% w/v,≥˜85% w/v, ≥˜90% w/v, or ≥˜95% w/v of the composition.

In certain aspects, the carrier component comprises two or moreconstituents wherein the total concentration/amount of the two or morecarrier component constituents is represented by theconcentrations/amounts provided above. In aspects, the carrier componentcomprises a single constituent wherein the single constituent is presentin an amount represented by the concentrations/amounts provided above.In certain aspects, the carrier component comprises a singleconstituent, the single constituent being water, or, e.g., water forinjection (WFI), wherein the water is present in an amount representing≥˜70% w/v, ≥˜75% w/v, ≥˜80% w/v, ≥˜85% w/v, ≥˜90% w/v, or ≥˜95% w/v ofthe composition. In aspects, the pharmaceutically acceptable andophthalmologically suitable compositions are aqueous compositions. Inaspects, compositions provided by the invention typically comprise atleast about 70% w/v water, and even more typically at least about 85%w/v-about 95% w/v water.

In common aspects, compositions are aqueous solutions or aqueous gels.In aspects, such aqueous compositions can be easily administered to therecipient such as by means of instilling one to two drops of thesolutions in affected eye(s). In aspects, the bimatoprost compound(s)and timolol compound(s) compositions are aqueous solutions. In aspects,the bimatoprost compound(s) and timolol compound(s) compositions areaqueous gel composition. In aspects, the aqueous compositions, whetherprovided as a solution or gel, are comprised of more than ˜50% w/vwater, e.g., more than ˜75% w/v, or, e.g., more than ˜90% w/v water andgenerally all, or all components of the formulation are fully dissolvedsuch that a clear, aqueous composition is provided.

In aspects, such amounts of a carrier component, carrier componentconstituents, or both, disclosed in this section represent an effectiveamount of a carrier component, carrier component constituent, or both.

In this and any other ingredient aspect of the invention, the inventionalso can be characterized as comprising a “means” for providing arecited function, here imparting/providing an effective, detectable, orsignificant carrier function (e.g., vehicle) to/of composition(s) of theinvention. In such a respect, any known equivalents of such named agentscan also be, e.g., are, incorporated into compositions or methods of theinvention. As with other sections similarly described herein, any of thecomponents of the invention can be, where suitable, described as means(e.g., the above-described carriers or components can be described ascarrier means or means for providing effective, detectable, orsignificant carrier or vehicle activity/characteristics to thecomposition.)

Compositions do not Include/are not Provided as/are SpecificallyProvided as

In aspects, compositions provided by the invention comprises at leasttwo active pharmaceutical ingredients, e.g., at least one API belongingto a PAC and at least one API belonging to a BBC. For example, inaspects, compositions do not comprise a sole PAC, e.g., a solebimatoprost compound, or a sole BBC, e.g., a sole timolol compound. Inaspects, compositions comprise no other API other than a bimatoprostcompound and a timolol compound. In aspects, compositions comprise nomore than two APIs, such as no API other than a PAC constituent (e.g., abimatoprost compound) and a BBC constituent (e.g., a timolol compound).For example, in certain aspects, compositions do not comprise a thirdAPI such as, e.g., travoprost or e.g., latanoprost. In aspects,compositions provided by the invention do not comprise analpha-adrenergic agonist. In aspects, each API of the compositionsprovided by the invention are provided in an amount capable of resultingin a detectable or significant therapeutic effect, e.g., are provided intherapeutic amounts. In aspects, compositions comprise a bimatoprostcompound in an amount less than 0.03% w/v, such as less than 0.02% w/v.In aspects, compositions comprise a timolol compound in an amount equalto or greater than at least about 0.3% w/v, such as greater than atleast about 0.4% w/v. In aspects, compositions comprise a timololcompound in an amount equal to or greater than about 0.5% w/v. Inaspects, compositions comprise a timolol compound in an amount equal toor greater than about 0.6% w/v. In aspects, compositions comprise abimatoprost compound in an amount no greater than about 0.02% w/v, suchas an amount no greater than about 0.015% w/v, e.g., no greater thanabout 0.01% w/v.

In aspects, compositions comprise an amount of sodium chloride greaterthan at least about 0.5% w/v, such as greater than about 0.6% w/v,greater than about 0.7% w/v, or, e.g., greater than 0.8% w/v. Inaspects, compositions comprise an amount of sodium chloride greater thanor equal to about 0.8% w/v.

In certain aspects, compositions comprise at least one preservativecompound, e.g., at least one compound demonstrating detectable orsignificant preservative property(ies) described herein. In aspects,composition(s) provided by the invention are not characterizable aspreservative-free. In aspects, compositions specifically comprise abenzalkonium chloride preservative. In certain aspects, compositionscomprise benzalkonium in an amount greater than at least about 0.001%w/v, such as at least greater than about 0.002% w/v, 0.003% w/v, or atleast greater than about 0.004% w/v. In certain aspects, compositionscomprise a preservative compound, e.g., benzalkonium chloride, in anamount not greater than about 0.007% w/v of the composition.

In aspects, compositions provided by the invention comprise at least onepenetration enhancing agent (providing detectable or significantincreased penetration into ocular tissue of at least one constituent ofa PAC, at least one constituent of a BBC, or both). In aspects,compositions comprise at least one penetration agent which is notbenzalkonium chloride. In aspects, compositions comprise at least onepenetration agent in addition to benzalkonium chloride.

In aspects, compositions provided by the invention comprise at least oneagent providing detectable or significant increased penetration intoocular tissue of at least one constituent of a PAC, at least oneconstituent of a BBC, or both which further provides detectablesolubilization effect. In aspects, compositions further comprise atleast one additional agent providing detectable solubilization effect,such that the composition(s) comprise at least two agents providingdetectable solubilization of a PAC constituent, BBC constituent, orboth.

In aspects, compositions do not comprise an antioxidant component (e.g.,a compound providing detectable or significant antioxidant activity).

In aspects, compositions do not comprise EDTA. In aspects, compositionsdo not comprise a chelation component (e.g., a compound providingdetectable or significant chelating activity).

In aspects, compositions do not comprise glycerol.

In aspects, compositions do not comprise more than 0.009% w/v of apolyvinyl alcohol. In aspects, compositions comprise no polyvinylalcohol. In aspects, compositions do not comprise, e.g., Mowiol, e.g.,Mowiol 4-88, Mowiol 8-88, or, e.g., Mowiol 18-88.

In aspects, compositions do not comprise a combination of compoundscomprising polyoxyl 40 hydrogenated castor oil, boric acid, propyleneglycol, sorbitol, and zinc chloride. In aspects, compositions do notcomprise a combination of compounds comprising disodium EDTA, glycerol,and polysorbate 80.

In aspects, a composition provided by the invention does not comprise anamount of free monosaccharide that results in a detectable orsignificant increase in bacterial growth or detectably or significantincrease in the tonicity of the composition (e.g., osmolality). Inaspect, a composition does not comprise more than about, e.g., 0.01%w/v, 0.001% w/v, 0.0001% w/v, 0.00001% w/v, 0.000001% w/v, or, e.g.,0.0000001% w/v of a free monosaccharide, e.g., glucose. In aspects,compositions can be characterized as essentially free or free (to thelimits of detection) of any of the compounds described in this paragraphor section. In aspects, compositions do not comprise more than about,e.g., 0.01% w/v, 0.001% w/v, 0.0001% w/v, 0.00001% w/v, 0.000001% w/v,or, e.g., 0.0000001% w/v of a free monosaccharide not characterizable asa sugar alcohol. In aspects, a tonicity component does not comprise anysuch amount of a constituent characterizable as a glucose compound,e.g., D-glucose (dextrose).

In certain aspects, compositions do not comprise a surfactant. Incertain aspects, compositions do not comprise any componentcharacterizable as a surfactant other than polysorbate 80. In aspects,compositions do not comprise one or more of chlorbutano thimerosal,phenylmercuric acetate phenylmurcuric nitrate, chloride components(e.g., stabilized chloride dioxide, etc.) or, e.g., mixtures thereof. Inaspects, compositions do not comprise one or more of polyvinyl alcohol,povidone (polyvinyl pyrrolidone), hydroxypropylmethyl cellulose (alsopresented as “hydroxypropyl methylcellulose” or “hydroxylpropyl methylcellulose”), polyxamers, carboxymethyl cellulose, hydroxyethylcellulose, or cyclodextrin.

Ratios

In aspects, one way to characterize compositions provided by theinvention is by the ratios of one or more components or constituents ofthe composition(s).

According to aspects, any component(s) or compound(s)/agent(s) describedherein can be present in composition(s) in therapeutically effectiveamount(s), compositionally compatible amount(s), or both. In aspects,any single component or compound/agent provided herein can be present ina relationship with, such as, e.g., in a ratio with, any one or moreother single component or compound/agent. In aspects, any combination ofcomponent(s) or compound(s)/agent(s) provided herein can be present in aratio with any other combination of component(s) orcompound(s)/agent(s). In aspects, ratio(s) between such component(s) orcompound(s)/agent(s) or combinations thereof can be established usingany provided amounts for each disclosed herein, including, e.g., valueswithin ranges of such amounts disclosed herein. To exemplify thisdisclosure, the following table is provided. Table 1 below, e.g.,illustrating a ratio array, demonstrates the types of ratios which thereader should understand to be encompassed by the disclosure herein. Asone example, a “PEC”, or “penetration enhancement component” can bepresent in composition(s) herein in a ratio with a “PAC”, or“prostaglandin analogue component”, such a ratio established by theamounts cited in the relevant disclosure for each of the penetrationenhancement component and prostaglandin analogue component herein.Further, as a PAC can be represented by a single compound, e.g.,bimatoprost, and as a penetration enhancement component can berepresented by a single compound, e.g., polysorbate 80, such a ratio canrepresent the relationship between such two compounds. Further, as apenetration enhancement component may be represented by a plurality ofcompounds, for example in aspects benzalkonium chloride and polysorbate80, such a ratio can represent the relationship between, e.g.,bimatoprost and the sum of the two penetration enhancement componentconstituents, wherein the values for such a ration are established bythe amounts cited in the relevant disclosure for each constituentherein.

TABLE 1 Exemplary component/constituent ratios. PAC BIM BBC TIM AAC BTCPVC PEC SZC DCC BFC TCC VEC CHC PHC AXC CRC PAC — BIM: BBC: TIM: AAC:BTC: PVC: PEC: SZC: DCC: BFC: TCC: VEC: CHC: PHC: AXC: CRC: PAC PAC PACPAC PAC PAC PAC PAC PAC PAC PAC PAC PAC PAC PAC PAC BIM PAC: — BBC: TIM:AAC: BTC: PVC: PEC: SZC: DCC: BFC: TCC: VEC: CHC: PHC: AXC: CRC: BIM BIMBIM BIM BIM BIM BIM BIM BIM BIM BIM BIM BIM BIM BIM BIM BBC PAC: BIM: —TIM: AAC: BTC: PVC: PEC: SZC: DCC: BFC: TCC: VEC: CHC: PHC: AXC: CRC:BBC BBC BBC BBC BBC BBC BBC BBC BBC BBC BBC BBC BBC BBC BBC BBC TIM PAC:BIM: BBC: — AAC: BTC: PVC: PEC: SZC: DDC: BFC: TCC: VEC: CHC: PHC: AXC:CRC: TIM TIM TIM TIM TIM TIM TIM TIM TIM TIM TIM TIM TIM TIM TIM TIM AACPAC: BIM: BBC: TIM: — BTC: PVC: PEC: SZC: DDC: BFC: TCC: VEC: CHC: PHC:AXC: CRC: AAC AAC AAC AAC AAC AAC AAC AAC AAC AAC AAC AAC AAC AAC AACAAC BTC PAC: BIM: BBC: TIM: AAC: — PVC: PEC: SZC: DDC: BFC: TCC: VEC:CHC: PHC: AXC: CRC: BTC BTC BTC BTC BTC BTC BTC BTC BTC BTC BTC BTC BTCBTC BTC BTC PVC PAC: BIM: BBC: TIM: AAC: BTC: — PEC: SZC: DDC: BFC: TCC:VEC: CHC: PHC: AXC: CRC: PVC PVC PVC PVC PVC PVC PVC PVC PVC PVC PVC PVCPVC PVC PVC PVC PEC PAC: BIM: BBC: TIM: AAC: BTC: PVC: — SZC: DDC: BFC:TCC: VEC: CHC: PHC: AXC: CRC: PEC PEC PEC PEC PEC PEC PEC PEC PEC PECPEC PEC PEC PEC PEC PEC SZC PAC: BIM: BBC: TIM: AAC: BTC: PVC: PEC: —DDC: BFC: TCC: VEC: CHC: PHC: AXC: CRC: SZC SZC SZC SZC SZC SZC SZC SZCSZC SZC SZC SZC SZC SZC SZC SZC DCC PAC: BIM: BBC: TIM: AAC: BTC: PVC:PEC: SZC: — BFC: TCC: VEC: CHC: PHC: AXC: CRC: DCC DCC DCC DCC DCC DCCDCC DCC DCC DCC DCC DCC DCC DCC DCC DCC BFC PAC: BIM: BBC: TIM: AAC:BTC: PVC: PEC: SZC: DDC: — TCC: VEC: CHC: PHC: AXC: CRC: BFC BFC BFC BFCBFC BFC BFC BFC BFC BFC BFC BFC BFC BFC BFC BFC TCC PAC: BIM: BBC: TIM:AAC: BTC: PVC: PEC: SZC: DDC: BFC: — VEC: CHC: PHC: AXC: CRC: TCC TCCTCC TCC TCC TCC TCC TCC TCC TCC TCC TCC TCC TCC TCC TCC VEC PAC: BIM:BBC: TIM: AAC: BTC: PVC: PEC: SZC: DDC: BFC: TCC: — CHC: PHC: AXC: CRC:VEC VEC VEC VEC VEC VEC VEC VEC VEC VEC VEC VEC VEC VEC VEC VEC CHC PAC:BIM: BBC: TIM: AAC: BTC: PVC: PEC: SZC: DDC: BFC: TCC: VEC: — PHC: AXC:CRC: CHC CHC CHC CHC CHC CHC CHC CHC CHC CHC CHC CHC CHC CHC CHC CHC PHCPAC: BIM: BBC: TIM: AAC: BTC: PVC: PEC: SZC: DDC: BFC: TCC: VEC: CHC: —AXC: CRC: PHC PHC PHC PHC PHC PHC PHC PHC PHC PHC PHC PHC PHC PHC PHCPHC AXC PAC: BIM: BBC: TIM: AAC: BTC: PVC: PEC: SZC: DDC: BFC: TCC: VEC:CHC: PHC: — CRC: AXC AXC AXC AXC AXC AXC AXC AXC AXC AXC AXC AXC AXC AXCAXC AXC CRC PAC: BIM: BBC: TIM: AAC: BTC: PVC: PEC: SZC: DDC: BFC: TCC:VEC: CHC: PHC: AXC: — CRC CRC CRC CRC CRC CRC CRC CRC CRC CRC CRC CRCCRC CRC CRC CRC ABBREVIATIONS: PAC (prostaglandin analogue component);BIM (bimatoprost compound); BBC (beta-adrenoreceptor antagonist(β-blocker) component); TIM (timolol compound); AAC (alternative oradditional anti-glaucoma agent(s) component, also referred to herein asan AGAC); PVC (preservative component); PEC (penetration enhancercomponent); SZC (solubilization component); DDC (demulcent component);BFC (buffer component); TCC (tonicity component); VEC (viscosityenhancer component); CHC (chelation component); PHC (pH adjustingcomponent); AXC (antioxidant component), CRC (carrier component).

Provided in Table 2 are exemplary amounts of exemplarycomponent(s)/ingredient(s), which, in aspects, can be/are present incomposition(s) provided by the invention in a ratio with any one or moreother component(s)/compound(s) disclosed, wherein such ratios can, inaspects, be in a ratio formed by such disclosed amounts.

TABLE 2 Exemplary Ingredients and Exemplary Amounts from Which Ratio(s)Can be Derived. Exemplary Component/Compound Exemplary Compound(s)Amount(s) Description (if component provided) (% w/v) ProstaglandinAnalogue Bimatoprost compound, 0.005-0.02 Component e.g., bimatoprostbase Beta-Adrenoreceptor Timolol compound, e.g.,  0.4-0.8 Antagonist(β-Blocker) timolol maleate Component Preservative ComponentBenzalkonium Chloride  0.003-0.007 Penetration Enhancer Polysorbate 80,TPGS, 0.25-2.5 Component Cremophor EL, Tromethamine (TRIS)Solubilization Polysorbate 80, TPGS, 0.25-2.5 Component Cremophor EL,Tromethamine (TRIS) Demulcent Component Polysorbate 80 0.25-2.5 BufferComponent Dibasic sodium phosphate, 0.005-0.6  citric acid monohydrateTonicity Component Mannitol, Sodium 0.005-6 Chloride (e.g., 0.005-1,2-6) Viscosity Enhancer Gellan Gum 0.1-1  Component Bimatoprost CompoundBimatoprost base 0.005-0.02 Timolol Compound Timolol maleate  0.4-0.8Polysorbate 80 — 0.25-2.5 TPGS — 0.25-2.5 Cremophor EL — 0.25-2.5Benzalkonium Chloride —  0.003-0.007 Sodium Chloride — 0.05-1.5 DibasicSodium — 0.01-0.5 Phosphate Citric Acid Monohydrate — 0.005-0.09Tromethamine — 0.05-1   Mannitol —  2-6 Gellan Gum — 0.1-1  Note: Inaspects, values in Table 2 represent the amounts of each respectivecomponent/ingredient's representative percentage by weight/volume (%w/v) of the composition(s). In other aspects, values in Table 3represent the amounts of each respective component/ingredient'srepresentative percentage by weight/weight (wt. %) of thecomposition(s).

In aspects, compositions provided by the invention comprise a ratio ofquaternary ammonium salt, e.g., benzalkonium chloride, to penetrationenhancer component of about 1:2 to about 1:2500, e.g., ˜1:100 to ˜1:300or ˜1:35 to ˜1:840, or, e.g., ˜1:200.

In aspects, compositions provided by the invention comprise a ratio ofbimatoprost compound, e.g., bimatoprost base, to timolol compound, e.g.,salt of timolol, e.g., timolol maleate, of about 1:2 to about 1:200,such as ˜1:2 to ˜1:100 or ˜1:20 to ˜1:160, e.g., ˜1:20-˜1:100,˜1:30-˜1:90, ˜1:40-˜1:80, ˜1:50-˜1:70, ˜1:60-˜1:70, ˜1:65-˜1:70, or,e.g., about 1:68.

In aspects, compositions provided by the invention comprise a ratio ofbimatoprost compound, e.g., bimatoprost base, to quaternary ammoniumsalt, e.g., benzalkonium chloride, of about 1:2 to about 200:1, such as,e.g., ˜1:2-˜100:1, ˜1:1-˜50:1, ˜1:1-˜20:1, ˜1:1-˜10:1, ˜1:1-˜5:1, or˜6.7:1 to ˜1:1.4, e.g., about 2:1.

In aspects, compositions provided by the invention comprise a ratio ofbimatoprost compound, e.g., bimatoprost base, to penetration enhancementcomponent of about 1:1 to about 1:500, ˜1:10-˜1:500, ˜1:12.5-˜1:500,such as ˜1:20 to ˜1:200, ˜1:30-˜1:180, ˜1:40-˜1:160, ˜1:50:˜1:140,˜1:60-˜1:120, ˜1:70-˜1:110, ˜1:80-˜1:110, ˜1:90-˜1:105, or, e.g., about1:12.5-about 1:500, e.g., about 1:100.

In aspects, compositions provided by the invention comprise a ratio oftimolol compound to quaternary ammonium salt, e.g., benzalkoniumchloride, of about 40:1 to about 1000:1, e.g., ˜50:1-˜500:1,˜50:1-˜400:1, ˜60:1-˜300:1, ˜70:1-˜200:1, or, e.g., such as about 100:1to about 500:1 or about 57:1-about 267:1, e.g., ˜100:1-˜150:1,˜120:1-˜140:1, such as, e.g., about 136:1.

In aspects, compositions provided by the invention comprise a ratio oftimolol compound, e.g., salt of timolol, e.g., timolol maleate, topenetration enhancer component of about 4:1 to about 1:6.25, such as,e.g., ˜3:1-˜1:6, ˜2:1-˜1:5, ˜1:1-˜1:4, ˜1:1-˜1:3, or, e.g., ˜1:1-˜1:2,such as, e.g., about 1:1-about 1:5, or ˜3:1-˜1:6.5, ˜3.2-˜1:6.3, or˜3.2:1 to about 1:6.25, e.g., about 2:1-about 1:3, e.g., about 1:1.5,or, e.g., about 1:1.47.

In aspects, compositions provided by the invention comprise a ratio ofthe total amount of API consisting of the bimatoprost compound, e.g.,bimatoprost base, and the timolol compound, e.g., salt of timolol, e.g.,timolol maleate, to quaternary ammonium salt, e.g., benzalkoniumchloride, of about 120:1 to about 4005:1, such as, e.g., ˜120:1-˜2000:1,˜120:1-˜1000:1, ˜120:1-˜500:1, ˜120:1-˜400:1, ˜120:1-˜300:1,˜120:1-˜200:1, or, e.g., ˜120:1-˜150:1, such as, e.g., ˜57:1 to ˜274:1,e.g., ˜140:1 or ˜138:1.

In aspects, compositions provided by the invention comprise a ratio ofthe total amount of API consisting of the bimatoprost compound, e.g.,bimatoprost base, and the timolol compound, e.g., salt of timolol, e.g.,timolol maleate, to penetration enhancement component of about 16:1 toabout 1:2.1, such as, e.g., ˜10:1-˜1:2, ˜5:1-˜1:2, or, e.g., ˜2:1-˜1:2,e.g., ˜1:1 to ˜1:10, ˜1:1-˜1:7, ˜1:1-˜1:6, ˜1:1-˜1:5, ˜1:2-˜1:5, or,e.g., ˜1:3-˜1:5, such as ˜3.3:1 to ˜1:6.2, e.g., ˜1:1.5 or ˜1:1.45.

In aspects, compositions provided by the invention comprise a ratio ofbimatoprost compound, e.g., bimatoprost base, to the viscosity enhancercomponent of about 1:2 to about 1:1000, such as, e.g., ˜1:2-˜1:500,˜1:2-˜1:400, ˜1:2-˜1:300, ˜1:2-˜1:200, or, e.g., ˜1:2-˜1:100, such as,e.g., ˜1:5-˜1:100, ˜1:10-˜1:100, ˜1:20-˜1:30-˜1:100, ˜1:40-˜1:90,˜1:50-˜1:80, or, e.g., ˜1:50-˜1:70, as in, e.g., ˜1:1 to ˜1:500 or ˜1:1to ˜1:100, such as, e.g., about 1:60.

In aspects, compositions provided by the invention comprise a ratio oftimolol compound, e.g., a salt of timolol, e.g., timolol maleate, to theviscosity enhancer component of about 10:1 to about 1:10, such as, e.g.,˜5:1 to ˜1:5, ˜4:1-˜1:4, ˜3:1-˜1:3, or ˜2:1 to ˜1:2, such as, e.g.,about 1.1:1 to about 1.15:1, or about 1.13:1.

In aspects, compositions provided by the invention comprise a ratio ofthe total amount of API consisting of the bimatoprost compound, e.g.,bimatoprost base, and the timolol compound, e.g., salt of timolol, e.g.,timolol maleate, to the viscosity enhancer component is about 10:1 toabout 1:10, such as, e.g., ˜5:1 to ˜1:5, ˜4:1-˜1:4, ˜3:1-˜1:3, or ˜2:1to ˜1:2, such as, e.g., as in, e.g., ˜2:1-˜1:1, ˜1.5:1-˜1:1,˜1.4:1-˜1:1, ˜1.3:1-˜1:1, or, e.g., ˜1.2:1-˜1:1, such as, e.g., ˜1.15:1.

Additional Means/Steps for Performinig Functions

In aspects, compositions provided by the invention comprise one or moremeans for performing one or more specific functions and methods of theinvention include steps for performing functions. In general, anyelement described herein as a “means” for performing a function canalso, wherever suitable, serve as a “step for” performing a function inthe context of methods of the invention, and vice versa. E.g., acomponent described herein as a means for preserving a composition alsosimultaneously and implicitly supports a method of making such acomposition comprising a step of preserving a composition and a kitcomprising a means for delivering a composition implicitly andsimultaneously provides a step for delivering the composition comprisingthe use of such delivery means.

In one aspect, compositions provided by the invention comprise means forpreserving the composition(s), e.g., detectably or significantlyinhibiting microbial growth, in aspects detectably or significantlyreducing the number of impurities or detectably or significantlyimproving the stability of the compositions such that compositionsremain safe and suitable for administration after storage of at leastabout 1 month, e.g., ˜2 months, or e.g., ˜3 months or more aftermanufacturing at room temperature (e.g., about 25° C. and about 60%relative humidity or, e.g., about 25° C. +/−2° C. and about 40% +/−5%relative humidity) (“preservation means”). Support for preservationmeans can be found in, e.g., the section entitled “PreservativeComponent (Preservation Agent(s)).”

In one aspect, compositions provided by the invention comprise means forenhancing penetration of one or more composition constituents, inaspects such means for penetration enhancement detectably orsignificantly improving the penetration into an eye tissue of one ormore active pharmaceutical ingredients, e.g., PAC constituent, BBCconstituent, or both, e.g., bimatoprost compound, e.g., bimatoprostbase, timolol compound, e.g., salt of timolol, e.g., timolol maleate, orboth (“penetration enhancement means”). Support for penetrationenhancement means can be found in, e.g., the section entitled“Penetration Enhancer Component (Penetration Enhancer(s)).”

In one aspect, compositions provided by the invention comprise means forsolubilization of one or more composition constituents, in aspects suchmeans for solubilization detectably or significantly improving thesolubilization of one or more composition constituents, e.g., one ormore active pharmaceutical ingredients, e.g., PAC constituent, BBCconstituent, or both, e.g., bimatoprost compound, e.g., bimatoprostbase, timolol compound, e.g., salt of timolol, e.g., timolol maleate, orboth, detectably or significantly maintaining the solubilization of oneor more composition constituents for a detectably or significantlylonger period of time, or both (“solubilization means”). Support forsolubilization means can be found in, e.g., the section entitled“Solubilization Component (Solubilizing Agent(s)).”

In one aspect, compositions provided by the invention comprise means forsolubilization of one or more composition constituents; in aspects, suchmeans for solubilization detectably or significantly improving thesolubilization of one or more composition constituents, e.g., one ormore active pharmaceutical ingredients, e.g., PAC constituent, BBCconstituent, or both, e.g., bimatoprost compound, e.g., bimatoprostbase, timolol compound, e.g., salt of timolol, e.g., timolol maleate, orboth; in aspects, such means detectably or significantly maintaining thesolubilization of one or more composition constituents for a detectablyor significantly longer period of time (than substantially similar oridentical compositions lacking such means—substantially similar in thisrespect and in some aspects typically meaning either about the sameamount, same amount, or significantly similar amount of most, generallyall, essentially all or all relevant ingredients), or both; and, furtheror alternatively, in aspects, detectably or significantly improving thepenetration into an eye tissue of one or more active pharmaceuticalingredients, e.g., PAC constituent, BBC constituent, or both, e.g.,bimatoprost compound, e.g., bimatoprost base, timolol compound, e.g.,salt of timolol, e.g., timolol maleate, or both (“penetrationenhancement and solubilization means”). Support for penetrationenhancement and solubilization means can be found in, e.g., the sectionentitled “Combination Solubilization/Penetration Enhancer Component(Solubilizing Agent(s)/Penetration Enhancer(s)).”

In one aspect, compositions provided by the invention comprise means forsoothing irritation caused by one or more composition constituents, suchmeans for soothing detectably or significantly reducing or preventingirritation or inflammation caused by one or more compositionconstituents (“demulcent means”). Support for demulcent means can befound in, e.g., the section entitled “Demulcent Component(Demulcent(s)).”

In aspects, compositions provided by the invention comprise a means ofbuffering a composition, in aspects such a means capable of maintainingthe pH of compositions between ˜6 and ˜8, such as, e.g., ˜6.2-˜7 or,e.g., ˜6.9-˜7.5, for an extended period of time, e.g., at least about 1month, ˜3 months, ˜6 months, ˜12 months, ˜18 months, ˜24 months, or,e.g., at least about 36 months when stored at about 15° C. to about 25°C. +/−2° C. In certain aspects, compositions provided by the inventionlack such a means of buffering pH (“buffering means”). In aspects, suchbuffering means are described in, e.g., the section entitled “BufferComponent (Buffer(s)).”

In one aspect, compositions provided by the invention comprise means forproviding a suitable tonicity of the composition(s), providing asuitable osmolality of the composition(s), e.g., means for providingcomposition(s) which, in aspects, do not cause detectable or significantocular irritation due to tonicity when provided according toinstructions (“tonicity means”). Support for tonicity means can be foundin, e.g., the section entitled “Tonicity Component (Tonicity Agent(s)).”

In one aspect, compositions provided by the invention comprise means forincreasing viscosity, such means for viscosity enhancement in aspectsdetectably or significantly increasing the thickness or viscosity of acomposition, or, e.g., detectably or significantly modifying the natureof the composition such as, e.g., providing the composition as a gel(“viscosity enhancer means” or “thickening means”). In aspects, suchmeans for increasing viscosity only do so (1) upon exposure to theenvironment of the mammalian eye to which it is administered, (2) uponexposure to temperatures of at least about 32 degrees Celsius (° C.),(3) upon exposure to an environment having an ionic strength detectablyor significantly greater than that of one or more gelling agents presentin the composition (e.g., gellan gum), (4) exposure to an environmenthaving a pH of greater than about 6.2, or (5) any combination of(1)-(4), over the viscosity of the composition while stored prior toadministration at a temperature of about 15° C. to about 25° C. +/−2°C.). Support for viscosity enhancer/thickening means can be found in,e.g., the section entitled “Viscosity Enhancer/Thickening Component(Viscosity Enhancing Agent(s)/Thickening Agent(s)).”

In one aspect, compositions provided by the invention comprise means forchelation, in aspects such means for chelation detectably orsignificantly improving the stability of one or more activepharmaceutical ingredients, e.g., one or more PAC constituents, BBCconstituents, or both, e.g., bimatoprost compound, e.g., bimatoprostbase, timolol compound, e.g., salt of timolol, e.g., timolol maleate, orboth, detectably enhancing the effectiveness of one or morepreservatives, or any combination thereof (“chelation means”). Supportfor chelation means can be found in, e.g., the section entitled“Chelation Component (Chelating Agent(s)).”

In one aspect, compositions provided by the invention comprise means foradjusting the pH of the composition(s), in aspects providing a suitableor target pH of the composition(s) of, e.g., about 6-about 8, e.g.,about 6.2-about 7, or, e.g., about 6.9-about 7.5 (“pH adjusting means”).Support for pH adjusting means can be found in, e.g., the sectionentitled “pH Adjusting Component (pH Adjusting Agent(s)).

In one aspect, compositions provided by the invention comprise means forprotecting API(s) from oxidation, e.g., means for providing antioxidantprotection of API(s), such means for antioxidant protection of API(s)which in aspects detectably or significantly improving the stability ofthe one or more bimatoprost compound(s), timolol compound(s), or both,detectably or significantly reducing impurities detected at time points2 weeks, 1 months, 2 months, or 3 months or more (e.g., 6, 12, 18, 24,or 36 months) after manufacturing, or any combination thereof(“antioxidant means”). Support for antioxidant means can be found in,e.g., the section entitled “Antioxidant Component (Antioxidant(s)).”

In one aspect, compositions provided by the invention comprise means forproviding compositions of the invention as liquid compositions (e.g.,solutions, gels, etc.), e.g., providing a carrier for the API(s) and anyone or more other excipients of the composition(s) (“carrier means”).Support for carrier means can be found in, e.g., the section entitled“Carrier Component (Carrier Agent(s)).”

Composition Characteristics Ready-to-Use

In aspects, compositions provided by the invention are provided inready-to-use (RTU) form, and do not require dilution or furthermodification prior to administration. In such compositions, thecomposition, in aspects, is stored in a healthcare setting, and is readyfor immediate administration to a subject, such as a human patient. Insuch compositions, the composition, in aspects, is stored in a homesetting, and is ready for immediate administration, e.g.,self-administration, to a subject.

pH

As used herein, the term “pH” is the conventional measurement unit ofhydrogen ion activity in a solution at room temperature (about 25° C.)unless another temperature is specified. In aspects, compositionsprovided by the invention have a pH of between about 6 and about 8.

In aspects, compositions provided by the invention have a pH of about 6to about 8, such as about 6 to about 7 or about 6 to about 7.5, such as,e.g., ˜6-˜7.4, ˜6-˜7.3, ˜6-˜7.2, ˜6-˜7.1, or ˜6-˜7, e.g., ˜6.1-˜8,˜6.2-˜8, ˜6.3-˜8, ˜6.4-˜8, ˜6.5-˜8, ˜6.6-˜8, ˜6.7-˜8, ˜6.8-˜8, ˜6.9-˜8,or, e.g., ˜7-˜8, for example ˜6.1-˜7.5, or ˜6.2-˜7.8, ˜6.2-˜7.5, or˜6.2-˜7.3 such as, e.g., ˜6.1-˜7.4, ˜6.2-˜7.2, or, e.g., about 6.2 to˜7, such as, e.g., ˜6.3, ˜6.4, ˜6.4, ˜6.6, ˜6.7, ˜6.8, or, e.g., ˜6.9.

In aspects, compositions provided by the invention have a pH of about 6to about 8, such as ˜6.5-˜8, or, e.g., about 6.9 to about 7.5, such as,e.g., ˜6.9-˜7.4, ˜6.9-˜7.3, or ˜6.9-˜7.2, e.g., ˜7-˜7.5, ˜7.1-˜7.5, or,e.g., ˜7.1-˜7.3.

In aspects, the pH of the compositions provided by the invention, suchas, e.g., bimatoprost and timolol compound compositions, will beaffected by the concentration of each of the ingredients duringmanufacturing. Hence, in aspects, the pH of the compositions can beadjusted during the manufacturing to attain the target pH rangesdescribed above, such as, e.g., ˜6.2-˜7, or alternatively ˜6.9-˜7.5,e.g., ˜7.1-˜7.3. In aspects, the pH of the compositions provided by theinvention is maintained from the time of establishment duringmanufacturing and the time of packaging to the time of administration tothe mammalian eye when stored at controlled room temperature, e.g., at atemperature of about 15° C. to 25° C. +/−2° C. or a temperature of about25° C. +/−2° C. and about 40% +/−5% relative humidity, for a period ofat least about 1 month, such as, e.g., for a period of about 1-about 36months or more.

Osmolality

In aspects, compositions provided by the invention are characterizableas isotonic. In aspects, compositions provided by the invention have anosmolality of about 171 milliosmoles per kilogram (mOsm/Kg) to about1171 mOsm/Kg, such as, e.g., ˜171 mOsm/Kg-˜1100 mOsm/Kg, ˜171mOsm/Kg-˜1000 mOsm/Kg, ˜171 mOsm/Kg-˜900 mOsm/Kg, ˜171 mOsm/Kg-˜800mOsm/Kg, ˜171 mOsm/Kg-˜700 mOsm/Kg, ˜171 mOsm/Kg-˜600 mOsm/Kg, ˜171mOsm/Kg-˜500 mOsm/Kg, or ˜171 mOsm/Kg-˜400 mOsm/Kg.

In some aspects, compositions provided by the invention have anosmolality of about 180 mOsm/Kg-about 1171 mOsm/Kg, such as, e.g., ˜200mOsm/Kg-˜1171 mOsm/Kg, ˜220 mOsm/Kg-˜1171 mOsm/Kg, ˜240 mOsm/Kg-˜1171mOsm/Kg, ˜260 mOsm/Kg-˜1171 mOsm/Kg, ˜280 mOsm/Kg-˜1171 mOsm/Kg, ˜300mOsm/Kg-˜1171 mOsm/Kg, ˜320 mOsm/Kg-˜1171 mOsm/Kg, ˜340 mOsm/Kg-˜1171mOsm/Kg, ˜360 mOsm/Kg-˜1171 mOsm/Kg, ˜380 mOsm/Kg-˜1171 mOsm/Kg, or,e.g., ˜400 mOsm/Kg-˜1171 mOsm/Kg, e.g., ˜200 mOsm/Kg-˜1000 mOsm/Kg.

In aspects, compositions provided by the invention have an osmolality ofabout 200 mOsm/Kg to about 500 mOsm/Kg, or, e.g., about 200 mOsm/Kg toabout 400 mOsm/Kg, such as, e.g., ˜250 mOsm/Kg-˜400 mOsm/Kg, ˜260mOsm/Kg-˜390 mOsm/Kg, ˜270 mOsm/Kg-˜380 mOsm/Kg, or, e.g., ˜280mOsm/Kg-˜370 mOsm/Kg, for example ˜210 mOsm/Kg-˜390 mOsm/Kg, ˜220mOsm/Kg-˜380 mOsm/Kg, ˜230 mOsm/Kg-˜370 mOsm/Kg, ˜240 mOsm/Kg-˜360mOsm/Kg, or, e.g., ˜250 mOsm/Kg-˜350 mOsm/Kg or ˜280 mOsm/Kg-˜370mOsm/Kg.

In aspects, the invention provides compositions comprising a tonicityagent component such that the composition comprises an isotonic range(e.g., an osmolality) within a range provided herein. In aspects, theosmolality of the pharmaceutically acceptable and ophthalmologicallysuitable formulations provided by the invention are advantageous in thatsuch isotonicity can be important to composition efficacy and patientcomfort, thus contributing to continued use of the composition, e.g.,tolerability of the composition for a longer period of time than acomposition comprising an osmolality either higher than or lower thanthat of the compositions described herein.

Viscosity

In aspects, compositions provided by the invention, after manufactureand while in storage at about 15° C.-about 27° C., have a viscosity ofless than about 75 cps, e.g., in aspects, a viscosity of less than about70 cps, less than about 65 cps, less than about 60 cps or less thanabout 50 cps. In aspects, compositions provided by the inventionformulated such that they are capable of forming a gel comprise aviscosity after manufacture and while in storage at about 15° C.-about27° C. have a viscosity which is detectably or significantly less thanthe viscosity of the composition after administration to a mammalianeye. That is, in aspects, compositions provided by the invention, whenprovided in the form of a composition capable of forming a gel, form agel having a viscosity after administration to a mammalian eye which isdetectably or significantly greater than the viscosity of thecomposition after manufacture and while in storage of about 15° C.-about27° C., prior to administration. In aspects, compositions afteradministration to a mammalian eye can comprise a viscosity of greaterthan about 15 cps, such as, e.g., ≥˜20 cps, ≥˜30 cps, ≥˜40 cps, ≥˜50cps, ≥˜60 cps, ≥˜70 cps, ≥˜80 cps, ≥˜90 cps, or, e.g., ≥˜100 cps. Inaspects, compositions have at least generally the same, at leastsubstantially the same, at least essentially the same, essentially thesame, or the same viscosity after administration to a mammalian eye asprior to administration (e.g., after manufacture and during storage at,e.g., about 15° C.-about 27° C.). In certain aspects, at any time duringstorage at about 15° C.-about 27° C. and after administration tomammalian eye, the composition has a viscosity of between about 1 andabout 150 cps, e.g., ˜1 cps-˜140 cps, ˜1 cps-˜130 cps, ˜1 cps-˜120 cps,˜1 cps-˜110 cps, or, e.g., in aspects, ˜1 cps-˜100 cps. In aspects,higher viscosity compositions can be advantageous (e.g., intolerability, effectiveness, stability, ease of administration or use,etc.). In aspects, a composition having a detectably or significantlyhigher viscosity than the composition in aqueous solution form whenstored at about 15° C.-about 27° C. can be advantageous. In aspects,such advantages may be, e.g., providing a detectable or significantimprovement in the ease of convenient administration, (e.g., make thecomposition easier for a user to apply), detectably or significantlyincreasing contact of the composition with eye tissue, or e.g.,detectably or significantly increasing the length of time thecomposition maintains contact with eye tissue following administration.In aspects, a detectable or significant difference in viscosity isachieved after a composition is applied to the eye. In aspects,compositions in the form of a gel detectably or significantly increasein viscosity upon contact with the eye over the viscosity of thecomposition prior to administration, e.g., when stored at about 15°C.-about 27° C., such as increasing in viscosity by at least about 10%,≥˜20%, ≥˜30%, ≥˜40%, ≥˜50%, ≥˜60%, ≥˜70%, ≥˜80%, ≥˜90%, or ≥˜100% ormore, such as ≥˜125%, ≥˜150%, ≥˜175%, ≥˜200%, or even more, such as,e.g., ≥˜400%, ≥˜600%, ≥˜800%, or, for example, ≥˜1000% or more. Inaspects, such an increased viscosity is advantageous for the reasonsprovided in this paragraph or, e.g., elsewhere herein.

Stability

Uncontradicted, the term “stable” or “stable composition” as usedherein, refers to a composition comprising both a PAC (e.g., comprisinga bimatoprost compound, e.g., bimatoprost base) and a BBC (e.g.,comprising a timolol compound, e.g., a salt of timolol, e.g., timololmaleate) provided by the invention having sufficient physical andchemical stability to allow storage at a convenient temperature, such asbetween about 0° C. and about 50° C. for a commercially reasonable orrelevant period of time.

In aspects, compositions of the invention are stable. In aspects,compositions of the invention exhibit physical stability, chemicalstability, or both, over any of the periods of storage described herein.The term “physical stability” typically refers to maintenance of color,dissolved oxygen level, head space oxygen level, and particulate matter,and the term “chemical stability” typically relates to formation ofdrug-related impurities in terms of total impurity, single maximumindividual impurity, and maximum individual unknown impurity. For thepurpose of the present invention chemical stability also includesmaintenance of pH of the finished formulation. In aspects, compositionsprovided by the invention demonstrate stability required forcommercially relevant times after manufacturing, such as for at leastabout 1, 3, 6, 9, 12, 18, 24 or 36 months, during which composition(s)is/kept in its/their original packaging under specified storagecondition. The term “shelf life” refers to the amount of time theophthalmic composition may be stored without detectable or significantloss of potency and/or dissolution profile. Preferably, the shelf liferefers to the amount of time the ophthalmic composition may be storedwithout a loss of more than 2%, 5%, 8% or 10% of the potency and/or lossof suitable dissolution. Compositions of the invention, in aspects,exhibit such shelf-life characteristic. Herein, uncontradicted, the term“room temperature” refers to controlled room temperature as about 15° C.to 25° C. +/−2° C.

In one aspect, the invention provides pharmaceutically acceptable andophthalmologically suitable compositions comprising less than about 2.5%of total impurities, such as, e.g., ≤˜2% total impurities, ≤˜1.5%, ≤˜1%,or ≤˜0.5% total impurities. The term “impurity” refers to an undesiredsubstance in a composition which may be present in an initialcomposition and/or may be formed after a certain period of shelf life ofa composition. These impurities may, e.g., be formed via degradation ofone or more components of the composition. Sources of degradation caninclude, but are not limited to, oxidation, light, ultraviolet light,moisture, heat, changes in pH, and composition component interactions.

In aspects, the invention provides compositions described herein,wherein the composition comprises less than about 2.5% total impurities,e.g., less than about 2%, less than about 1.5%, less than about 1%, or,e.g., less than about 0.5% total impurities after storage at about 25°C. +/−2° C. and about 40% +/−5% relative humidity; about 40° C. +/−2° C.and not more than about 25% relative humidity; about 15° C.-about 27° C.and about 60% relative humidity; about 38° C.-about 42° C. and 75%relative humidity; or when stored under any such condition, or asequential combination of such conditions, for a period of at leastabout 1 month, e.g., ˜3 months, ≥˜6 months, ≥˜9 months, ≥˜12 months,≥˜14 months, ≥˜16 months, ≥˜18 months, ≥˜20 months, ≥˜22 months, ≥˜24months, ≥˜26 months, ≥˜28 months, ≥˜30 months, ≥˜32 months, ≥˜34 months,or, e.g., ≥˜36 months.

In one aspect, the invention provides pharmaceutically acceptable andophthalmologically suitable compositions which remain stable and retainat least about 90%, such as, e.g., ≥˜92%, ≥˜94%, ≥˜96%, ≥˜98%, or even≥˜99% of the labelled concentration of bimatoprost compound, e.g.,bimatoprost base, the labelled concentration of timolol compound, e.g.,timolol maleate, or both the labelled concentration of bimatoprost andtimolol compounds after storage under typical and/or acceleratedconditions.

In aspects, the invention provides compositions as described herein,wherein the composition maintains at least about 98%, e.g., at leastabout 99%, of the bimatoprost compound, the timolol compound, or bothwhen stored at about 25° C. +/−2° C. and about 40% +/−5% relativehumidity; about 40° C. +/−2° C. and not more than about 25% relativehumidity; about 15° C.-about 27° C. and about 60% relative humidity;about 38° C.-about 42° C. and 75% relative humidity; or when storedunder any such condition, or a sequential combination of suchconditions, for at least about one month, such as, e.g., ≥˜3 months, ≥˜6months, ≥˜9 months, ≥˜12 months, ≥˜14 months, ≥˜16 months, ≥˜18 months,≥˜20 months, ≥˜22 months, ≥˜24 months, ≥˜26 months, ≥˜28 months, ≥˜30months, ≥˜32 months, ≥˜34 months, or, e.g., ≥˜36 months.

Dosage Forms & Administration Rates

In aspects, compositions provided by the invention are pharmaceuticallyacceptable and ophthalmologically suitable compositions provided as atopically applied composition. In aspects, pharmaceutically acceptableand ophthalmologically suitable compositions provided by the inventioncan be provided as, e.g., formulated as, solutions, suspensions,ointments, creams, gels, sprays, and other dosage forms suitable fortopical ophthalmic administration. In aspects, compositions herein areprovided as topically applied solution compositions. In aspects,compositions herein are provided as topically applied gel compositions,or, e.g., compositions which form a gel upon administration (e.g., uponexposure to a sufficient amount of heat, e.g., body or ophthalmictemperature(s)). In some aspects, compositions provided by the inventionare injectable compositions or are formulated to be suitable foradministration by injection. In aspects, compositions provided by theinvention can be suitable for topical delivery as drops or implantationin or on a subject's eye or tissue surrounding the eye, e.g., suitablefor implantation into a subconjunctival space, naso-lacrimal duct, orvitreous body of the subject.

In aspects, compositions provided by the invention are aqueoussolutions. In aspects, compositions provided as aqueous solutionsprovide ease of use of such compositions including as a patient'sability to easily administer such compositions by means of instilling asuitable dose of the solutions to affected eye(s). In aspects, aqueouscompositions provided by the invention are typically more than about 50%w/v, e.g., ≥˜55% w/v, ≥˜60% w/v, ≥˜65% w/v, ≥˜70% w/v, ≥˜75% w/v, ≥˜80%w/v, ≥˜85% w/v, or ≥˜90% w/v water, and at least generally all,substantially all, or all components of the formulation are fullydissolved such that a clear, aqueous solution (or, in aspects, e.g., aclear, aqueous gel) is provided.

In aspects, pharmaceutically acceptable and ophthalmologically suitablecompositions provided by the invention are provided as a liquidsolution, wherein compositions are administered as drops to affectedeye(s). In aspects, compositions are administered as about 1 to about 3drops, such as, e.g., about 1 to about 2 drops, e.g., about 1, about 2,or about 3 drops of the composition to each affected eye perdose/administration. Typically, a single administration comprises nomore than about 2 drops of composition, such as about 1 or about 2 dropsof composition per administration. In aspects, exact amounts to beadministered can be determined by an overseeing physician, e.g.,optometrist. In aspects, a typical drop size is between about 5 μL andabout 100 μL, such as, e.g., ˜5 μL-˜75 μL, or ˜5 μL-about 50 μL, suchas, e.g., ˜10 μL-˜100 μL or, e.g., ˜25 μL-˜100 μL, for example ˜25μL-˜70 μL, or, e.g., ˜20 μL-˜60 μL.

In aspects, compositions provided herein can be administered in doses of1-3 drops, such as no more than 3 drops, no more than 2 drops, or, e.g.,no more than 1 drop one or twice per day (e.g., once or twice per24-hour period). In aspects, compositions herein are administered as 1-2drops once or twice daily. In aspects, compositions herein areadministered as 1-2 drops once daily (e.g., once per 24-hour period). Inaspects, compositions herein are administered as a single drop once ortwice daily. In aspects, compositions herein are administered as asingle drop once daily (e.g., once per 24-hour period). In aspects,compositions comprising bimatoprost and timolol compounds areadministered to the mammalian eye once daily as 1-2 drops, e.g., as asingle drop, either in the morning or in the evening.

In certain aspects, pharmaceutically acceptable and ophthalmologicallysuitable compositions provided by the invention are provided as a gel.In aspects, compositions provided as a gel increase the amount of timethe composition contacts eye tissue, leading to, in aspects, anincreased bioavailability of active ingredient(s) contained therein(i.e., a detectable or significant improvement in bioavailability of theAPI(s)).

In aspects, pharmaceutically acceptable and ophthalmologically suitablecompositions provided by the invention as gel compositions areadministered as drops to affected eye(s). In aspects, compositions areadministered as about 1 to about 3 drops, such as, e.g., about 1 toabout 2 drops, e.g., about 1, about 2, or about 3 drops of thecomposition to each affected eye per dose/administration. Typically, asingle administration comprises no more than about 2 drops ofcomposition, such as about 1 or about 2 drops of composition peradministration. In aspects, exact amounts to be administered can bedetermined by an overseeing physician, e.g., optometrist. In aspects, atypical drop size is between about 5 μL and about 100 μL, such as, e.g.,˜5 μL-˜75 μL, or ˜5 μL-about 50 μL, such as, e.g., ˜10 μL-˜100 μL or,e.g., ˜25 μL-˜100 μL, for example ˜25 μL-˜70 μL, or, e.g., ˜20 μL-˜60μL.

According to certain aspects, pharmaceutically acceptable andophthalmologically suitable compositions provided by the invention arecontrolled release compositions, such as, e.g., characterizable asslow-release compositions.

In some aspects, compositions are administered as a singleadministration. In other aspects, compositions are administered as aplurality of administrations, such as, e.g., 5, 10, 20, 30, 40, or 50 ormore administrations, such as, e.g., daily administration for a periodof days, weeks, months, or years (e.g., 1, 2, 3, 4, or 5 years orlonger). In aspects, multiple administrations are separated from oneanother by a period of at least about 1 minute, such as at least about30 minutes or longer, such as, e.g., at least about 1 hour or longer, orsuch as 24 hours or longer.

In aspects, an effective treatment period is a period of about 1 day,about 1 day-about 1 week, about 5 days to about 1 month, about 1 week toabout 3 months, about 2 weeks to about 3 months, about 1 month to about6 months, about 3 months to about 9 months, about 6 months to about 12months (1 year), about 9 months to about 18 months, about 12 months toabout 24 months, about 18 months to about 30 months, about 24 months toabout 36 months, or about 1 year to about 3 years, or longer, e.g., aperiod of greater than about 1 year, greater than about 2 years, greaterthan about 3 years, greater than about 4 years, or greater than about 5years. In certain aspects, compositions provided by the invention areused as a chronic treatment, e.g., in treating a chronic condition, suchthat the effective treatment period is ongoing with no defined endpoint. In aspects, compositions provided by the invention are used intreatment of a chronic condition, wherein treatment is for a period ofat least about 1 year or longer, e.g., ≥˜2 years, ≥˜3 years, ≥˜4 years,or ≥˜5 years or longer, e.g., ≥˜5, ≥˜10, ≥˜15, ≥˜20, or ≥˜25 years ormore.

In aspects, ophthalmic compositions described herein can be applied toeach affected eye; to both eyes; or, e.g., the dominant eye of therecipient over the course of an effective treatment period. Exactapplication may, in aspects, vary depending on the target indication,the tolerance or goals of the recipient, the aim of the attendingphysician/treatment provider, or any combination thereof.

Methods of Use

In aspects, the invention provides methods of using any one or more ofthe compositions described herein in methods of treating one or moreocular conditions, one or more symptoms related to one or more ocularconditions, or any combination thereof. Exemplary methods are providedhere. In aspects, performance of one or more methods described hereinresults in a significant reduction in elevated intraocular pressure in atreated mammalian eye.

In aspects, the invention provides any one or more of the methodsdescribed in this section, wherein the administration of thecomposition, when administered in an effective amount (e.g., amountsdisclosed herein), for an effective treatment period (e.g., treatmentperiods described herein), results in a detectable or significantimprovement in vision; detectable or significant modulation of one ormore physiological properties of the eye; detectable or significantreduction in intraocular pressure; detectable or significant treatmentof glaucoma, e.g., open-angle glaucoma or any one or more symptomsrelated to glaucoma described herein, or any combination of suchresults.

Method of Improving Vision

In one aspect, the invention provides pharmaceutically acceptable andophthalmologically suitable compositions comprising a bimatoprostcompound and a timolol compound and methods for their use in improvingvision, reducing visual impairment, treating a vision-related ophthalmiccondition, or combinations thereof. In aspects, such an effect isattained via the detectable or significant reduction in intraocularpressure. In aspects, compositions provided by the invention and methodsof their use described herein can be provided to or for any patient inneed thereof or suffering from a condition benefiting from the provisionof compositions or methods described herein. In aspects, a suitablepatient is a patient, e.g., a mammal, such as, e.g., a human, sufferingfrom elevated intraocular pressure, glaucoma (e.g., open-angleglaucoma), elevated intraocular pressure associated with glaucoma, orcombination(s) thereof. In aspects, a suitable patient is a patient forwhom prior treatment with one or more single prostaglandin analogues hasproven insufficient to treat their condition. In aspects, a suitablepatient is a patient for whom prior treatment with one or more singlebeta-adrenoreceptor antagonists (β-blockers) has proven insufficient totreat their condition.

In aspects, compositions provided by the invention are suitable foradministration to any subject benefiting from the administrationthereof, e.g., any mammal with an ophthalmic condition benefitting fromthe receipt of a suitable amount of such compositions. In aspects, asuitable recipient is an adult human. In aspects, a suitable patient isa patient for whom prior treatment with one or more single prostaglandinanalogues and one or more single beta-adrenoreceptor antagonists hasproven insufficient.

In aspects, compositions provided by the invention are suitable foradministration to children (in this and similar other aspects,“suitability” or “suitable for” in regards to characteristics of acomposition refers to, i.a., the characteristic of demonstratedsuitability in terms of efficacy and safety, e.g., demonstrated throughclinical trials to be sufficiently suitable (safe and effective) totreat the indicated condition, act in the indicated population/setting,or both, e.g., in a significant number of patients in such studies). Inaspects, compositions provided by the invention are not suitable foradministration to children. In aspects, compositions provided by theinvention are suitable for administration to children for whom otherinterventions are unsuitable, undesirable, or insufficient.Determinations of suitable and efficacy in such aspects can bedetermined by, e.g., scientific evidence, such as, for example,determination of bioequivalence to a product having such effects, ordetermination of such effectives through one or more scientific studies,such as one or more adequate, well-controlled, studies, which would besuitable for submission to US FDA in connection with approval of apharmaceutical product, wherein a suitably significant effect isobserved.

Method of Modulating Physiological Properties of the Eye; ReducingIntraocular Pressure; Treating Glaucoma

In one aspect, the invention provides a method of detectably orsignificantly modulating one or more physiological properties of amammalian eye comprising administering a therapeutically effectiveamount of any one or more compositions described herein. In aspects, theinvention provides a method of detectably or significantly reducingintraocular pressure in a mammalian eye comprising administering atherapeutically effective amount of any one or more compositionsdescribed herein. In aspects, the invention provides a method ofdetectably or significantly slowing the rate of increase of intraocularpressure in a mammalian eye comprising administering to a patientbenefitting therefrom a therapeutically effective amount of any one ormore compositions described herein. In aspects, the invention providesmethods of detectably or significantly slowing glaucoma progression,e.g., open-angle glaucoma progression or, e.g., improving or slowing theprogression of one or more symptoms related to glaucoma, e.g., openangle glaucoma, such as, e.g., elevated intraocular pressure, visionimpairment, vision loss, seeing halos around lights, rainbow-coloredcircles around lights, light sensitivity, ocular redness, hazyappearance of the eye (e.g., whitening of the cornea), upset stomach orvomiting, eye pain, loss of peripheral or side vision, patchy blindspots inside or central vision, tunnel vision, headaches, and any othersymptoms related to glaucoma comprising administering a therapeuticallyeffective amount of any one or more compositions described herein. Inaspects, the invention provides methods of treating glaucoma, e.g.,open-angle glaucoma, in a mammalian eye comprising administering to apatient diagnosed with glaucoma or suffering from clinical symptom(s) ofglaucoma a therapeutically effective amount of any one or morecompositions described herein.

In aspects, the invention provides the methods described abovecomprising administering to the recipient/patient a therapeuticallyeffective amount of a pharmaceutically acceptable and ophthalmologicallysuitable ophthalmic composition, e.g. provided in the form of asolution, comprising (1) about 0.005% w/v-about 0.02% w/v of abimatoprost compound; (2) about 0.4% w/v-about 0.8% w/v of a timololcompound; (3) about 0.003%-about 0.007% of a quaternary ammonium salt;and (4) about 0.25% w/v-about 2.5% w/v of a penetration enhancercomponent. In aspects, the ratio of the quaternary ammonium salt to thepenetration enhancer component in the composition is about 1:35-about1:840. In aspects, the ratio of the bimatoprost compound to thepenetration enhancer component is about 1:12.5-about 1:500. In aspects,the ratio of the timolol compound to the penetration enhancer componentis between about 3.2:1-1:6.3. In aspects, compositions can comprise anycombination of such ratios described here. In aspects, the compositionis stable when stored at about 25° C. +/−2° C. and about 40% +/−5%relative humidity; about 40° C. +/−2° C. and not more than about 25%relative humidity; about 15° C.-about 27° C. and about 60% relativehumidity; about 38° C.-about 42° C. and 75% relative humidity; or whenstored under any such condition, or a sequential combination of suchconditions, for at least about 1 month, e.g., at least about 2 months,at least about 3 months, at least about 2-about 6 months, about 3-about9 months, about 6-about 12 months, about 9-about 18 months, about12-about 24 months, about 18-about 30 months, about 24-about 36 months,or, e.g., for at least about 36 months.

In aspects, the invention provides the methods described abovecomprising administering to the recipient/patient a therapeuticallyeffective amount of a pharmaceutically acceptable and ophthalmologicallysuitable ophthalmic composition, e.g., provided in the form of a gel. Inaspects, such composition(s) are composition(s) comprising (1) about0.005% w/v-about 0.02% w/v of a bimatoprost compound; (2) about 0.4%w/v-about 0.8% w/v of a timolol compound; (3) about 0.003%-about 0.007%of a quaternary ammonium salt; and (4) about 0.25% w/v-about 2.5% w/v ofa penetration enhancer component. In aspects the ratio of the quaternaryammonium salt to the penetration enhancer component in the compositionis about 1:35-about 1:840. In aspects, the ratio of the bimatoprostcompound to the penetration enhancer component in the composition isabout 1:12.5-about 1:500. In aspects, the ratio of the timolol compoundto the penetration enhancer component in the composition is betweenabout 3.2:1-1:6.3. In aspects, the ratio of bimatoprost compound, e.g.,bimatoprost base, to the viscosity enhancer component in the compositionis about 1:2 to about 1:1000. In aspects, the ratio of timolol compound,e.g., a salt of timolol, e.g., timolol maleate, to the viscosityenhancer component in the composition is about 10:1 to about 1:10. Inaspects, the ratio of the total amount of API consisting of thebimatoprost compound, e.g., bimatoprost base, and the timolol compound,e.g., salt of timolol, e.g., timolol maleate, to the viscosity enhancercomponent in the composition is about 10.5:1 to about 1:9.9. In aspects,composition(s) comprise any one or more such ratio(s) described here. Inaspects, the composition is stable when stored at about 25° C. +/−2° C.and about 40% +/−5% relative humidity; about 40° C. +/−2° C. and notmore than about 25% relative humidity; about 15° C.-about 27° C. andabout 60% relative humidity; about 38° C.-about 42° C. and 75% relativehumidity; or when stored under any such condition, or a sequentialcombination of such conditions, for at least about 1 month, e.g., atleast about 2 months, at least about 3 months, at least about 2-about 6months, about 3-about 9 months, about 6-about 12 months, about 9-about18 months, about 12-about 24 months, about 18-about 30 months, about24-about 36 months, or, e.g., for at least about 36 months.

In aspects, the invention provides the methods described abovecomprising administering to the recipient/patient a therapeuticallyeffective amount of a pharmaceutically acceptable and ophthalmologicallysuitable ophthalmic composition, e.g., provided in the form of a gelcomprising (1) about 0.005% w/v-about 0.02% w/v of a bimatoprostcompound; (2) about 0.4% w/v-about 0.8% w/v of a timolol compound; (3)about 0.003%-about 0.007% of a quaternary ammonium salt. In aspects, theviscosity of the composition detectably or significantly increases (a)upon exposure to the environment of the mammalian eye to which it isadministered, (b) upon exposure to temperatures of at least about 32degrees Celsius (° C.), (c) upon exposure to an environment having anionic strength detectably or significantly greater than that of one ormore gelling agents present in the composition (e.g., gellan gum), (d)exposure to an environment having a pH of greater than about 6.2, or (e)any combination of (a)-(e), over the viscosity of the composition whilestored prior to administration at a temperature of between about 15° C.to about 25° C. +/−2° C.). In aspects, (a) the ratio of bimatoprostcompound, e.g., bimatoprost base, to the viscosity enhancer component isabout 1:2 to about 1:1000; (b) the ratio of timolol compound, e.g., asalt of timolol, e.g., timolol maleate, to the viscosity enhancercomponent is about 10:1 to about 1:10; (c) the ratio of the total amountof API consisting of the bimatoprost compound, e.g., bimatoprost base,and the timolol compound, e.g., salt of timolol, e.g., timolol maleate,to the viscosity enhancer component is about 10:1 to about 1:10; or (d)any combination of (a)-(c) are true. In aspects, compositions compriseany combination of such characteristics described in this paragraph. Inaspects, the composition is stable when stored at about 25° C. +/−2° C.and about 40% +/−5% relative humidity; about 40° C. +/−2° C. and notmore than about 25% relative humidity; about 15° C.-about 27° C. andabout 60% relative humidity; about 38° C.-about 42° C. and 75% relativehumidity; or when stored under any such condition, or a sequentialcombination of such conditions, for at least about 1 month, e.g., atleast about 2 months, at least about 3 months, at least about 2-about 6months, about 3-about 9 months, about 6-about 12 months, about 9-about18 months, about 12-about 24 months, about 18-about 30 months, about24-about 36 months, or, e.g., for at least about 36 months.

In aspects, a physiological property of a mammalian eye that istreated/modified or modulated by methods of the invention can be anyphysiological property participating in, affecting, contributing to,affected by, impaired by, damaged by, or otherwise associated with anophthalmic condition treatable with the compositions herein, e.g.,ocular conditions comprising as an element of its clinical presentation,elevated intraocular pressure, such as, e.g., glaucoma (for example,open-angle glaucoma).

In one specific aspect, the invention provides pharmaceuticallyacceptable and ophthalmologically suitable compositions comprisingbimatoprost compound(s) and timolol compound(s), wherein thecompositions are used in methods described herein, e.g., in a method ofreducing elevated IOP in adult patients with open-angle glaucoma orocular hypertension who have demonstrated an insufficient response totopical beta-blockers or prostaglandin analogues when administeredalone, or, e.g., in a method of treating glaucoma, e.g., open-angleglaucoma, in adult patients who have demonstrated an insufficientresponse to topical beta-blockers or prostaglandin analogues whenadministered alone, wherein the method(s) comprise(s) administering tothe patient a composition described herein in an effective amount for aneffective administration period, e.g., 1-2 drops once or twice daily fora period of at least 1 day, e.g., at least one week, at least one month,at least one year, at least 2 years, at least 3 years, at least 4 years,or 5 years or longer.

Exemplary Improvement(s)

In aspects, the invention provides a method of detectably orsignificantly reducing elevated intraocular pressure, the methodcomprising administering an effective amount, e.g., 1-2 drops ofcomposition provided once or twice daily, the composition being any oneor more of the compositions described herein, for an effective treatmentperiod, e.g., about 1 day to about 5 years or longer. In aspects, thedegree or extent of intraocular pressure elevation is improved after atreatment period of at least about 24 hours, e.g., ≥˜2 days, ≥˜3 days,≥˜4 days, ≥˜5 days, ≥˜6 days, ≥˜1 week, ≥˜2 weeks, ≥˜3 weeks, ≥˜1months, ≥˜6 weeks, ≥˜2 months, ≥˜10 weeks, or ≥˜3 months is about 95%,˜90%, ˜85%, ˜80%, ˜75%, ˜70%, ˜60%, ˜55%, ˜50%, ˜45%, ˜40%, ˜35%, ˜30%,˜25%, ˜20%, ˜15%, or ˜10% (or, in aspects, less) compared to the degreeor extent of elevated intraocular pressure at the start of treatment(or, e.g., the degree of intraocular pressure present withouttreatment).

In aspects, the invention provides a method of detectably orsignificantly slowing the rate of intraocular pressure increase, themethod comprising administering an effective amount, e.g., 1-2 drops ofcomposition provided once or twice daily, the composition being any oneor more of the compositions described herein, for an effective treatmentperiod, e.g., about 1 day to about 5 years or longer. In aspects, therate of intraocular pressure elevation is improved (e.g., rate ofintraocular pressure is slowed or reduced) after a treatment period ofat least about 24 hours, e.g., ≥˜2 days, ≥˜3 days, ≥˜4 days, ≥˜5 days,≥˜6 days, ≥˜1 week, ≥˜2 weeks, ≥˜3 weeks, ≥˜1 months, ≥˜6 weeks, ≥˜2months, ≥˜10 weeks, or ≥˜3 months is about 95%, ˜90%, ˜85%, ˜80%, ˜75%,˜70%, ˜60%, ˜55%, ˜50%, ˜45%, ˜40%, ˜35%, ˜30%, ˜25%, ˜20%, ˜15%, or˜10% (or, in aspects, less) compared to the rate of intraocular pressureincrease being experienced at the start of treatment (or, e.g., the rateof intraocular pressure increase present without treatment).

In certain aspects, a single administration of a composition provided bythe invention detectably or significantly reduces intraocular pressurefor a period of at least about 1 hour, such as, e.g., ≥˜2 hours, ≥˜4hours, ≥˜6 hours, ≥˜8 hours, ≥˜10 hours, ≥˜12 hours, ≥˜14 hours, ≥˜16hours, ≥˜18 hours, ≥˜20 hours, ≥˜22 hours, ≥˜24 hours, ≥˜26 hours, ≥˜28hours, ≥˜30 hours, ≥˜32 hours, ≥˜34 hours, ≥˜36 hours, ≥˜38 hours, ≥˜40hours, ≥˜42 hours, ≥˜44 hours, ≥˜46 hours, or ≥˜48 hours. In aspects,such improvement is in a significant number of patients, as determinedby one or more adequate and well-controlled clinical studies. Thisprinciple can be applied to any other clinical/therapeuticimprovement/effect described in this disclosure.

In aspects, the invention provides a method of treating glaucoma, e.g.,open-angle glaucoma, the method comprising administering an effectiveamount, e.g., 1-2 drops of composition provided once or twice daily, thecomposition being any one or more of the compositions described herein,for an effective treatment period, e.g., about 1 day to about 5 years orlonger. In aspects, the degree or extent of glaucoma is improved after atreatment period of at least about 24 hours, e.g., ≥˜2 days, ≥˜3 days,≥˜4 days, ≥˜5 days, ≥˜6 days, ≥˜1 week, ≥˜2 weeks, ≥˜3 weeks, ≥˜1months, ≥˜6 weeks, ≥˜2 months, ≥˜10 weeks, or ≥˜3 months is about 95%,˜90%, ˜85%, ˜80%, ˜75%, ˜70%, ˜60%, ˜55%, ˜50%, ˜45%, ˜40%, ˜35%, ˜30%,˜25%, ˜20%, ˜15%, or ˜10% (or, in aspects, less) compared to the degreeor extent of glaucoma at the start of treatment (or, e.g., the degree ofintraocular pressure present without treatment).

In aspects, the invention provides a method of detectably orsignificantly slowing the progression of glaucoma, the method comprisingadministering an effective amount, e.g., 1-2 drops of compositionprovided once or twice daily, the composition being any one or more ofthe compositions described herein, for an effective treatment period,e.g., about 1 day to about 5 years or longer. In aspects, the rate ofglaucoma progression is improved (e.g., rate of glaucoma progression isslowed or reduced) after a treatment period of at least about 24 hours,e.g., ≥˜2 days, ≥˜3 days, ≥˜4 days, ≥˜5 days, ≥˜6 days, ≥˜1 week, ≥˜2weeks, ≥˜3 weeks, ≥˜1 months, ≥˜6 weeks, ≥˜2 months, ≥˜10 weeks, or ≥˜3months is about 95%, ˜90%, ˜85%, ˜80%, ˜75%, ˜70%, ˜60%, ˜55%, ˜50%,˜45%, ˜40%, ˜35%, ˜30%, ˜25%, ˜20%, ˜15%, or ˜10% (or, in aspects, less)compared to the rate of glaucoma progression being experienced at thestart of treatment (or, e.g., the rate of intraocular pressure increasepresent without treatment).

In certain aspects, a single administration of a composition provided bythe invention detectably or significantly reduces or improves (asapplicable) one or more clinical indicators of glaucoma for a period ofat least about 1 hour, such as, e.g., ≥˜2 hours, ≥˜4 hours, ≥˜6 hours,≥˜8 hours, ≥˜10 hours, ≥˜12 hours, ≥˜14 hours, ≥˜16 hours, ≥˜18 hours,≥˜20 hours, ≥˜22 hours, ≥˜24 hours, ≥˜26 hours, ≥˜28 hours, ≥˜30 hours,≥˜32 hours, ≥˜34 hours, ≥˜36 hours, ≥˜38 hours, ≥˜40 hours, ≥˜42 hours,≥˜44 hours, ≥˜46 hours, or ≥˜48 hours. In aspects, such improvement isin a significant number of patients, as determined by one or moreadequate and well-controlled clinical studies. This principle can beapplied to any other clinical/therapeutic improvement/effect describedin this disclosure.

In aspects, the invention provides methods of using the compositionsdescribed herein, e.g., within the “Methods of Use” section of thisdetailed description of the invention, wherein the methods compriseadministration of an effective amount of the composition, wherein theeffective amount about 1-about 2 drops, such as, e.g., about 1 drop, ofthe composition administered to a mammalian eye once or twice daily,e.g., for example once daily, over an effective treatment period (e.g.,exemplary effective treatment periods disclosed elsewhere herein), andthe method is optionally repeated for a number of times demonstrated toprovide a significant clinical effect in a significant number ofpatients in a well-controlled and adequate study or that is shown to bebioequivalent to a product that has been demonstrated to achieve the atleast substantially the same, generally the same, or effectively thesame clinical effect.

In aspects, the invention provides the methods described herein, whereinthe method comprises the administration of a composition comprising botha bimatoprost compound and a timolol compound and the method is capableof detectably or significantly reducing elevated intraocular pressure ina recipient suffering therefrom but who was previously demonstrated asbeing insufficiently responsive to a topical beta-blocker administeredalone, a prostaglandin analogue administered alone, or both.

Comparable or Improved Effects/Reduced Side Effects

In aspects, compositions described herein can be characterized inreference to a reference composition. In aspects, references tocomparator compositions relative to a comparison of effect(s) should beinterpreted as being demonstrated by one or more well-controlled andadequate clinical studies performed in compliance with generallyprevailing regulatory authority standards. Herein, a prevailingregulatory authority standard can be established by, e.g., a recognizedregulatory authority such as, e.g., the United States Food and DrugAdministration (US FDA).

In aspects compositions herein, methods of using compositions herein, orboth, are clinically demonstrated to be as effective or detectably orsignificantly more effective than treatment of the same or at leastessentially the same, generally the same, or the same condition with acomposition (e.g., a reference composition) or method comprising use ofa composition (e.g., a reference composition), as determined by one ormore well-controlled and adequate clinical studies performed incompliance with generally prevailing regulatory authority standards. Inaspects, reference to a “reference composition” herein includes anycomposition demonstrating bioequivalence to that reference composition.In aspects, a reference composition herein includes any compositiondemonstrating clinical equivalence to that reference composition.

In aspects, compositions described herein, methods of using compositionsherein, or both, demonstrate clinical equivalence as measured by any oneor more clinical parameters known in the art for the target indicationto any reference composition described herein or any composition havingdemonstrated bioequivalence to any reference composition describedherein.

In aspects, compositions described herein, methods of using compositionsherein, or both, demonstrate clinical superiority as measured by any oneor more clinical parameters known in the art for the target indicationto any reference composition described herein or any composition havingdemonstrated bioequivalence to any reference composition describedherein.

In aspects, compositions herein, methods of using compositions herein,or both, demonstrate at least equivalent or, in aspects, detectably orsignificantly greater biological effect, to one or more referencecompositions described herein, or e.g., to any composition or methods oftheir use having demonstrated bioequivalence to any referencecomposition described herein, as measured by one or more bioequivalenceindicators (such as, e.g., one or more pharmacokinetic data parametersknown in the art).

In aspects, compositions described herein, methods of using compositionsherein, or both, demonstrate bioequivalence as measured by any one ormore pharmacokinetic parameters known in the art for the targetindication to any reference composition described herein or to anycomposition having demonstrated bioequivalence to any referencecomposition described herein.

In aspects, compositions described herein, methods of using compositionsherein, or both, demonstrate bioequivalence as determined by applicableUnited States Food and Drug Administration (US FDA) standards to anyreference composition described herein or to any composition havingdemonstrated bioequivalence to any reference composition describedherein.

In aspects, compositions described herein, methods of using compositionsherein, or both, demonstrate superior biological effect as measured byany one or more pharmacokinetic parameters known in the art for thetarget indication to any reference composition described herein or toany composition having demonstrated bioequivalence to any referencecomposition described herein.

In aspects, one reference composition is a composition comprising, e.g.,consisting of, 0.3 mg/mL (0.03% w/v) bimatoprost, 6.8 mg/mL (0.68% w/v)timolol maleate (an amount equivalent to 5 mg/mL or 0.5% w/v timolol),0.05 mg (0.005% w/v) benzalkonium chloride, sodium chloride, sodiumphosphate dibasic heptahydrate, citric acid monohydrate, hydrochloricacid and/or sodium hydroxide, and water, a composition approved asEuropean Medicines Agency product number EMEA/H/C/000668 (first grantedmarketing authorization valid throughout the European Union on May 19,2006), having the marketed product name “GANFORT®”. See, e.g., thewebsite ema.europa.eu/en/medicines/human/EPAR/ganfort#product-information-section. Herein, reference to GANFORT® should beinterpreted as the product approved as European Medicines Agency productnumber EMEA/H/C/000668, having receive such first granted marketingauthorization valid throughout the European Union on May 19, 2006; theproduct described in “Ganfort: EPAR—Product Information”, firstpublished on May 3, 2010 and last updated on Sep. 1, 2021 (available viathe website cited above); the product marked in Europe as GANFORT® as ofthe date of this filing, or any combination thereof.

In aspects, one reference composition is a composition comprising, e.g.,consisting of, 0.1 mg/mL (0.01% w/v) bimatoprost; timolol maleate in anamount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v)benzalkonium chloride; optionally one or more of sodium chloride, sodiumphosphate dibasic heptahydrate, citric acid monohydrate, hydrochloricacid and/or sodium hydroxide; and water. In aspects, such a compositionis identifiable as, e.g., “Bimat LS TM Eye Drops” by Ajanta Pharma. Inaspects, such a composition is a composition equivalent to thecomposition identifiable as “Bimat LS TM Eye Drops” by Ajanta Pharma.

In aspects, the invention provides methods of treatment provided herein,such as, e.g., a method of improving vision in a mammalian eye, a methodof modulating one or more physiological properties of a mammalian eye, amethod of reducing intraocular pressure, a method of treating glaucomaor one or more symptoms related thereto, or any combination thereof,wherein the method is clinically demonstrated to be as effective ordetectably or significantly more effective than treatment of the same orat least essentially the same, generally the same, or the same conditionwith about the same amount of a composition (e.g., a referencecomposition) comprising or, e.g., consisting of, 0.3 mg/mL (0.03% w/v)bimatoprost, 6.8 mg/mL (0.68% w/v) timolol maleate (an amount equivalentto 5 mg/mL or 0.5% w/v timolol), 0.05 mg (0.005% w/v) benzalkoniumchloride, sodium chloride, sodium phosphate dibasic heptahydrate, citricacid monohydrate, hydrochloric acid and/or sodium hydroxide, and waterfor the same or similar indication (e.g., reducing IOP) and for at leastsubstantially the same administration period as determined by one ormore well-controlled and adequate clinical studies performed incompliance with generally prevailing regulatory authority standards. Inaspects, the invention provides methods of treatment provided herein,such as, e.g., a method of improving vision in a mammalian eye, a methodof modulating one or more physiological properties of a mammalian eye, amethod of reducing intraocular pressure, a method of treating glaucoma,or any combination thereof, wherein the method is clinicallydemonstrated to be as effective or detectably or significantly moreeffective than treatment of the same condition with about the sameamount of a reference composition consisting of 0.3 mg/mL (0.03% w/v)bimatoprost, 6.8 mg/mL (0.68% w/v) timolol maleate (an amount equivalentto 5 mg/mL or 0.5% w/v timolol), 0.05 mg (0.005% w/v) benzalkoniumchloride, sodium chloride, sodium phosphate dibasic heptahydrate, citricacid monohydrate, hydrochloric acid and/or sodium hydroxide, and waterfor the same or similar indication (e.g., reducing IOP) and for at leastsubstantially the same administration period as determined by one ormore well-controlled and adequate clinical studies performed incompliance with generally prevailing regulatory authority standards.

In aspects, the invention provides methods of treatment provided herein,such as, e.g., a method of improving vision in a mammalian eye, a methodof modulating one or more physiological properties of a mammalian eye, amethod of reducing intraocular pressure, a method of treating glaucoma,or any combination thereof, wherein the method is clinicallydemonstrated to be as effective or detectably or significantly moreeffective than treatment of the same or at least essentially the same,generally the same, or the same condition with about the same amount ofthe product approved as European Medicines Agency product numberEMEA/H/C/000668 for the same or similar indication (e.g., reducing IOP)and for at least substantially the same administration period.

In aspects, the invention provides methods of treatment provided herein,such as, e.g., a method of improving vision in a mammalian eye, a methodof modulating one or more physiological properties of a mammalian eye, amethod of reducing intraocular pressure, a method of treating glaucoma,or any combination thereof, wherein the method is clinicallydemonstrated to be as effective or detectably or significantly moreeffective than treatment of the same or at least essentially the same,generally the same, or the same condition with about the same amount ofa composition, e.g., a reference composition, comprising, or, e.g.,consisting of, 0.1 mg/mL (0.01% w/v) bimatoprost; timolol maleate in anamount equivalent to 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v)benzalkonium chloride; optionally one or more of sodium chloride, sodiumphosphate dibasic heptahydrate, citric acid monohydrate, hydrochloricacid and/or sodium hydroxide; and water for the same or similarindication (e.g., reducing TOP) and for at least substantially the sameadministration period. In aspects, the invention provides methods oftreatment provided herein, such as, e.g., a method of improving visionin a mammalian eye, a method of modulating one or more physiologicalproperties of a mammalian eye, a method of reducing intraocularpressure, a method of treating glaucoma, or any combination thereof,wherein the method is clinically demonstrated to be as effective ordetectably or significantly more effective than treatment of the samecondition with about the same amount of a composition consisting of, 0.1mg/mL (0.01% w/v) bimatoprost; timolol maleate in an amount equivalentto 5 mg/mL (0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v) benzalkoniumchloride; optionally one or more of sodium chloride, sodium phosphatedibasic heptahydrate, citric acid monohydrate, hydrochloric acid and/orsodium hydroxide; and water for the same or similar indication (e.g.,reducing IOP) and for at least substantially the same administrationperiod.

In aspects, the invention provides methods of treatment provided herein,such as, e.g., a method of improving vision in a mammalian eye, a methodof modulating one or more physiological properties of a mammalian eye, amethod of reducing intraocular pressure, a method of treating glaucoma,or any combination thereof, wherein the method comprises use of acomposition described herein, and the method results in a population oftreated subjects, on average, maintaining a longer course of therapythan the course of therapy tolerated by a comparable population oftreated subjects, on average, treated with (1) the product approved asEuropean Medicines Agency product number EMEA/H/C/000668; (2) acomposition comprising, consisting at least generally of, substantiallyof, essentially of, or consisting of, 0.3 mg/mL (0.03% w/v) bimatoprost,6.8 mg/mL (0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mLor 0.5% w/v timolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide, and water (3) acomposition comprising or, e.g., consisting at least generally of,substantially of, essentially of, or consisting of, 0.1 mg/mL (0.01%w/v) bimatoprost; timolol maleate in an amount equivalent to 5 mg/mL(0.5% w/v) timolol; 0.1 mg/mL (0.01% w/v) benzalkonium chloride;optionally one or more of sodium chloride, sodium phosphate dibasicheptahydrate, citric acid monohydrate, hydrochloric acid and/or sodiumhydroxide; and water; (4) an ophthalmic composition demonstratingessentially the same, generally the same, or the same intraocularpressure reduction capability, (5) ophthalmic compositions comprising ahigher amount of benzalkonium chloride, bimatoprost compound, timololcompound, or any combination thereof, or (6) any combination thereof, asdetermined by one or more well-controlled and adequate clinical studiesperformed in compliance with generally prevailing regulatory authoritystandards.

In aspects, the invention provides methods of treatment provided herein,such as, e.g., a method of improving vision in a mammalian eye, a methodof modulating one or more physiological properties of a mammalian eye, amethod of reducing intraocular pressure, a method of treating glaucoma,or any combination thereof, wherein the method comprises administrationof an effective amount of a composition described herein, and wherein aneffective amount is, e.g., about 1-about 2 drops of the compositionadministered once or twice daily over an effective treatment period, andwherein the method results in detectably or significantly reducedfrequency of (as experienced by a single user, reported as an average ofa population of users, or both), one or more of hyperemia, ocularredness, ocular burning, ocular itching, ocular stinging, conjunctivalirritation (irritation of the conjunctiva), sensitivity to light, eyepain, sticky eye(s), dry eye(s), sensation that something is in therecipient's eye(s), detectable or significant breaks in the surface ofthe eye either with or without associated inflammation, detectable orsignificant reduction in clear vision, redness and itching of theeyelid(s), hair growth around treated eye(s), darkening of theeyelid(s), darkening of the skin color around the treated eye(s),eyelash lengthening, ocular irritation, eye watering, swollen eyelid(s),reduced vision, runny nose, headache, abnormal sensation(s) in theeye(s), iris inflammation, swollen conjunctiva, painful eyelid(s), tiredeye(s), ingrown (in-growing) eyelash(es), darkening iris color, sunkeneye appearance, separation of the eyelid from the surface of the eye,eyelash darkening, shortness of breath, conjunctival hyperemia, tearfilm instability, loss of goblet cells, conjunctival squamous metaplasiaand apoptosis, disruption of the corneal epithelium barrier, damage todeep ocular tissue, cystoid macular oedema (retinal swelling leading toworsening vision), eye swelling, blurred vision, ocular discomfort,difficulty breathing/wheezing, symptoms of allergic reaction (swelling,redness of the eye and rash of the skin) or hypersensitivity, changes intaste sensation, dizziness, slowing of heart rate, high blood pressure,difficulty sleeping, nightmare, asthma, hair loss, periocular skindiscoloration, and tiredness, or detectably or significantly reducedabsorption of BKC by soft contact lenses, compared to treatment of thesame or at least essentially the same, generally the same, or the samecondition with about the same amount of (1) the product approved asEuropean Medicines Agency product number EMEA/H/C/000668; (2) acomposition comprising, consisting at least generally of, substantiallyof, essentially of, or consisting of, 0.3 mg/mL (0.03% w/v) bimatoprost,6.8 mg/mL (0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mLor 0.5% w/v timolol), 0.05 mg (0.005% w/v) benzalkonium chloride, sodiumchloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide, and water; (3) acomposition comprising, consisting at least generally of, substantiallyof, essentially of, or consisting of, 0.1 mg/mL (0.01% w/v) bimatoprost;timolol maleate in an amount equivalent to 5 mg/mL (0.5% w/v) timolol;0.1 mg/mL (0.01% w/v) benzalkonium chloride; optionally one or more ofsodium chloride, sodium phosphate dibasic heptahydrate, citric acidmonohydrate, hydrochloric acid and/or sodium hydroxide; and water, or(4) any combination thereof, for at least substantially the sameadministration period, such as that which may be reported by one or moreusers or determined by an appropriately controlled clinical trialrecognized by a prevailing regulatory authority, such as the UnitedStates Food and Drug Administration (US FDA).

Methods of Manufacturing

In one aspect, the invention provides a process for preparing apharmaceutically acceptable and ophthalmologically suitable compositionin the form of a solution. In aspects, the method ofmanufacture/manufacturing comprises a process for preparing apharmaceutically acceptable and ophthalmologically suitable compositionin the form of a solution comprising (1) about 0.005% w/v-about 0.02%w/v of a bimatoprost compound; (2) about 0.4% w/v-about 0.8% w/v of atimolol compound; (3) about 0.003%-about 0.007% of a quaternary ammoniumsalt; and (4) about 0.25% w/v-about 2.5% w/v of a penetration enhancercomponent. In aspects, the invention provides a process for preparing apharmaceutically acceptable and ophthalmologically suitable compositionin the form of a gel comprising (1) about 0.005% w/v-about 0.02% w/v ofa bimatoprost compound; (2) about 0.4% w/v-about 0.8% w/v of a timololcompound; (3) about 0.003%-about 0.007% of a quaternary ammonium salt;(4) about 0.25% w/v-about 2.5% w/v of a penetration enhancer component;and (5) about 0.1% w/v-about 1% w/v of a viscosity enhancer component.In aspects, the invention provides a process for preparing apharmaceutically acceptable and ophthalmologically suitable compositionin the form of a gel comprising (1) about 0.005% w/v-about 0.02% w/v ofa bimatoprost compound; (2) about 0.4% w/v-about 0.8% w/v of a timololcompound; (3) about 0.003%-about 0.007% of a quaternary ammonium saltand (4) about 0.1% w/v-about 1% w/v of a viscosity enhancer component.

In aspects, such composition(s) and related method(s) of theirmanufacture is/are characterized by lacking one, two, or more ofelements or steps provided here, comprising such elements but indifferent effective amounts, or, e.g., comprising such recited elementshowever providing such elements in a different order than describedhere. In certain aspects, one or more steps provided here may beeliminated.

In aspects, compositions are prepared by using any suitable technique,many of which are known to those skilled in the art, the steps of whichcan be combined in any order. In describing methods of manufacturingprovided by the invention, references to order of operations/steps maybe present. It should be understood that steps of describedmanufacturing process(es) can be performed in any suitable order,provided that the end product is at least substantially, at leastgenerally, or essentially the same.

According to certain aspects, the invention provides a method ofmanufacturing (e.g., a manufacturing process) for compositions describedherein, wherein the process is a non-aseptic process, and wherein themethod of manufacturing comprises a terminal sterilization step. Inaspects, compositions are terminally sterilized using moist heat.Terminal sterilization can be used to destroy all viable microorganismswithin the final, sealed container containing the pharmaceuticalcomposition. In aspects, an autoclave is used to accomplish terminalheat-sterilization of compositions in their final packaging. Typicalautoclave cycles in the pharmaceutical industry to achieve terminalsterilization of the final product are about 121° C. for at least about10 minutes. In aspects, facilities, equipment, procedures, and personnelparticipating in the method of manufacturing, e.g., participating in theprocessing, meet GMP rules and guidelines for non-aseptic processes.

According to alternative aspects, the invention provides a method ofmanufacturing (e.g., a manufacturing process) for compositions describedherein, wherein the process is an aseptic process. In aspects, sterilityis maintained during the manufacturing process by use of sterilematerials and a controlled working environment. In aspects, allcontainers and apparatus utilized in the process are sterilized,preferably by heat sterilization, prior to use, e.g., prior to filling.In aspects, a sterilized container is filled under aseptic conditions,such as by passing the composition through a filter, e.g., a sterilizingfilter. Therefore, in aspects, the compositions can be sterile filledinto a container to avoid the heat stress of terminal sterilization. Inaspects, facilities, equipment, procedures, and personnel participatingin the method of manufacturing, e.g., participating in the processing,meet GMP rules and guidelines for aseptic processing.

In aspects, the invention provides a method of manufacturing acomposition described herein, wherein the method comprises (1)preparation of a bulk composition, (2) offline filtration of the bulkcomposition, (3) online filtration of the bulk composition, and (4)final packaging of the composition. In aspects, composition(s) resultingfrom the method can be used in any one or more of the methods oftreatment described herein.

In aspects, the invention provides a method of manufacturing acomposition described herein, wherein the method comprises (1)preparation of a polymer phase, (2) preparation of a drug phase, (3)filtration of the drug phase into the polymer phase, (4) filtering thecomposition resulting from (3), and (5) final packaging of thecomposition. In aspects, composition(s) resulting from the method can beused in any one or more of the methods of treatment described herein.

In aspects, the invention provides pharmaceutically acceptable andophthalmologically suitable compositions comprising bimatoprostcompound(s), bimatoprost base, and timolol compound(s), e.g., a salt oftimolol, e.g., timolol maleate, and methods of their manufacture,wherein the composition resulting from the method of manufacturing isaseptically distributed into single-dose or multidose containers.Further, in aspects, the invention provides packaging of such single ormultidose containers into kits for distribution to an end user.

Specific examples of manufacturing process(es) suitable formanufacturing compositions provided by the invention are found in, e.g.,Example 3 and Example 4 of this disclosure.

According to some aspects, the invention provides a first method ofmanufacturing a composition described herein comprising the followingsteps.

In aspects, the invention provides a manufacturing process comprisingthe preparation of a bulk solution.

In aspects, preparation of a bulk solution comprises collecting water,e.g., WFI, in a manufacturing vessel at a temperature of about 65° C. toabout 85° C., such as, e.g., about 70° C.-about 80° C., or, e.g., notless than about 70° C. In aspects, the method comprises cooling thewater for injection to about 15° C. to about 30° C., such as about 20°C.-about 25° C. In aspects, the method comprises bubbling 0.2 μmfiltered nitrogen through the WFI. In aspects, the method comprisesbubbling 0.2 μm filtered nitrogen through the WFI until the dissolvedoxygen content of the WFI is less than or equal to about 2 ppm, such as,e.g., ≤˜1.5 ppm, ≤˜1 ppm, or, e.g., ≤˜0.5 ppm. In aspects, themanufacturing process comprises continuing to bubble 0.2 μm filterednitrogen through the WFI during bulk solution manufacturing.

In aspects, preparation of a/the bulk solution comprises transferring anamount, e.g., an amount of about 60-about 80 Kg, of WFI, e.g., about 70Kg of WFI, into a separate holding vessel. In aspects, this reserved WFIcan be used in other manufacturing steps, such as, e.g., the preparationof pH adjusting agents (such as, e.g., 0.1N hydrochloric acid, 0.1Nsodium hydroxide, or both), and for, e.g., bringing the finalcomposition up to a final target volume.

In aspects, bulk solution preparation comprises mixing the WFI with asuitable mixing device/stirrer, set at a speed appropriate for attainingsufficient mixing. In aspects, mixing speed can be adjusted according tothe vessel geometry and mixing/stirring dynamics exhibited by thesolution/composition throughout manufacture.

In aspects, bulk solution preparation comprises adding the requiredquantity of a preservation agent, e.g., benzalkonium chloride. Inaspects, the container comprising the preservation agent, e.g.,benzalkonium chloride to be added is rinsed one or more times, e.g.,once, twice, three times, four times, or, e.g., five times, with asufficient amount of WFI sufficient to rinse the container, e.g., anamount such as, e.g., about 30 mL to about 70 mL, or, e.g., about 50 mLeach time. In aspects, mixing/stirring is continued during the additionof the rinse solution back into the vessel after each rinse.

In aspects, bulk solution preparation comprises adding the requiredquantity of solubilizer, penetration enhancer, or compound(s) providingboth a solubilization and penetration enhancement effect, e.g.,polysorbate 80, tocopherol polyethylene glycol succinate (TPGS),polyoxyl castor oil (e.g., polyethyoxylated castor oil, such as polyoxyl35 castor oil, or, e.g., protein/peptide penetration enhancer(s) such aspoly-arginine or polyserine). In aspects, such ingredient(s) is/areadded, and the container(s) used to add the ingredient(s) is/are rinsedone or more times, e.g., once, twice, three times, four times, or, e.g.,five times, with an amount of WFI sufficient to rinse the container,e.g., an amount such as, e.g., about 30 mL to about 70 mL, or, e.g.,about 50 mL each time. In aspects, mixing/stirring is continued duringthe addition of the rinse solution back into the vessel after eachrinse.

In aspects, the total required quantity of PAC, e.g., a bimatoprostcompound, such as bimatoprost base, is added. In aspects, suchingredient(s) is/are added, and the container(s) used to add theingredient(s) is/are rinsed one or more times, e.g., once, twice, threetimes, four times, or, e.g., five times, with an amount of WFIsufficient to rinse the container, e.g., an amount such as, e.g., about20 mL to about 70 mL, or, e.g., about 25 mL or about 50 mL each time. Inaspects, mixing/stirring is continued during the addition of the rinsesolution back into the vessel after each rinse. In aspects, stirring iscontinued for at least about 15 minutes, such as at least about 30minutes, at least about 45 minutes, at least about 60 minutes, or atleast about 65 minutes, or for a sufficient time to ensure completedissolution of the timolol compound and composition uniformity.

In aspects, the total required quantity of BBC, such as, e.g., timololcompound, e.g., a salt of timolol, e.g., timolol maleate, is added. Inaspects, such ingredient(s) is/are added, and the container(s) used toadd the ingredient(s) is/are rinsed one or more times, e.g., once,twice, three times, four times, or, e.g., five times, with an amount ofWFI sufficient to rinse the container, e.g., an amount such as, e.g.,about 20 mL to about 70 mL, or, e.g., about 25 mL or about 50 mL eachtime. In aspects, mixing/stirring is continued during the addition ofthe rinse solution back into the vessel after each rinse. In aspects,stirring is continued for at least about 15 minutes, such as at leastabout 30 minutes, at least about 45 minutes, at least about 60 minutes,or at least about 65 minutes, or for a sufficient time to ensurecomplete dissolution of the timolol compound and composition uniformity.

In aspects, the volume of the composition in the manufacturing vessel isbrought up to about 90 L (e.g., about 90 Kg) using previously reservedWFI. In aspects, the resulting solution is stirred for at least about 15minutes, such as at least about 20 minutes, at least about 25 minutes,at least about 30 minutes, or, e.g., at least about 35 minutes or for asufficient time to ensure composition uniformity.

In aspects, bulk solution preparation comprises adding the requiredamount of a first buffer agent(s), such as, e.g., a phosphate buffer,e.g., dibasic sodium phosphate (heptahydrate), citrate buffer (e.g.,citric acid monohydrate), borate buffer or, e.g., acetate buffer. Inaspects, dibasic sodium phosphate is added. In aspects, mixing/stirringis continued during the addition of the components, and is continued fora sufficient period of time to ensure the buffer constituents arecompletely dissolved, such as, for example, a period of time of, e.g.,about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes,about 25 minutes, about 30 minutes, etc. In aspects, additionalmanufacturing step(s) continue once composition uniformity is ensured byvisual inspection of the bulk solution for clarity.

In aspects, bulk solution preparation comprises adding a required amountof a second buffer agent(s), such as, e.g., a phosphate buffer, e.g.,dibasic sodium phosphate (heptahydrate), citrate buffer (e.g., citricacid monohydrate), borate buffer or, e.g., acetate buffer. In aspects,citric acid monohydrate is added. In aspects, mixing/stirring iscontinued during the addition of the components, and is continued for asufficient period of time to ensure the buffer constituents arecompletely dissolved, such as, for example, a period of time of, e.g.,about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes,about 25 minutes, about 30 minutes, etc. In aspects, additionalmanufacturing step(s) continue once composition uniformity is ensured byvisual inspection of the bulk solution for clarity.

In aspects, bulk solution preparation can continue by adding therequired amount of tonicity agent(s), such as, e.g., sodium chloride. Inaspects, mixing/stirring is continued during the addition of thecomponents and is continued for a sufficient period of time to ensurethe buffer constituents are completely dissolved, such as, for example,a period of time of, e.g., about 5 minutes, about 10 minutes, about 15minutes, about 20 minutes, about 25 minutes, or at least about 30minutes or more. In aspects, composition uniformity is ensured byinspecting for visual clarity of the solution.

In aspects, preparation of the bulk solution is pH adjusted using one ormore pH adjusting agents. In aspects, pH of the solution is adjusted bythe addition or one or more pH adjusting agents, with the solutionsufficiently mixed after each addition such that the composition has auniform pH prior to (1) sampling for pH, and (2) applying further pHadjustment as needed. In aspects, pH is adjusted to a pH of about6.9-about 7.5, such as, e.g., about 7-about 7.4, e.g., about 7.1 toabout 7.3 using the pH adjusting agent(s).

In aspects, preparation of the bulk solution comprises bringing up thevolume of the solution to a final volume of, e.g., about 100 L, with WFIreserved as described above. In aspects, the resulting solution is mixedfor a sufficient period of time to ensure composition uniformity, suchas, e.g., a period of at least about 10 minutes, at least about 15minutes, at least about 20 minutes, at least about 25, or at least about30 minutes. In aspects, a final pH check is performed to ensure that thecomposition pH is about 6.9-about 7.5, such as, e.g., about 7-about 7.4,e.g., about 7.1 to about 7.3.

In aspects, once preparation of a/the bulk solution is complete, offlinefiltration is performed. In aspects, the filtration is performed underlaminar air flow.

In aspects, after completion of the preparation of the bulk solution,the filtration process is initiated under controlled conditions, suchas, e.g., under laminar air flow (LAF). In aspects, prior to initiationof the filtration process, a cartridge filter, e.g., a 0.2 μm capsule orcartridge filter, is integrity tested using an industry standardintegrity test, such as, e.g., a water bubble point test, against thefilter manufacturer's specification. In one aspect, an exemplaryacceptable result is a pressure of not less than about 46 psi under afiltration pressure limit of about 0.8 kg/cm² to about 1.8 kg/cm².

In aspects, prior to the start of filtration activity, the filtrationunit is flushed with a sufficient amount of bulk solution to flush theunit, such as, e.g., about 200-250 mL, e.g., about 180 mL, about 200 mL,about 210 mL, about 220 mL, or e.g., about 230 mL of the bulk solution.In aspects, the bulk solution can be held inside of the filtration unitfor a period of time during the flush, such as about 1.5 minutes, about2 minutes, about 2.5 minutes, or about 3 minutes during the flush. Inaspects, the bulk solution used for the flush is discarded after theflush. In aspects, the flushing procedure is repeated a number of times,such as one more time, two more times, three more times, four moretimes, or five or more times. In aspects, flushing is conducted a totalof about 3 times.

In aspects, upon completion of flushing, filtration of a/the bulksolution is initiated. In aspects, the bulk solution is filtered throughthe pre-sterilized, tested, and flushed 0.2 μm capsule or cartridgefilter, e.g., a polyethersulfone (PES) capsule filter. In aspects, allfiltrate is collected in a sterile receiving vessel.

In aspects, upon completion of filtration, the filtrate within thesterile receiving vessel is overlayed with nitrogen, such as, e.g., 0.2μm-filtered nitrogen.

In aspects, the receiving vessel can be transferred to a storage area,e.g., a sterile storage area, and stored under controlled conditions,e.g., controlled temperature and air flow conditions (e.g., underlaminar air flow) until initiation of the filling activity.

In aspects, a post-filtration integrity test of the filter can beperformed. In aspects, the post-filtration integrity test of the filtercan be a water bubble point test. In aspects, an acceptable result is apressure of not less than 39.2 psi under a filtration pressure limit ofabout 0.8 kg/cm² to about 1.8 kg/cm².

In certain aspects, completion of a/the first filtration process isfollowed by a second filtration, wherein, prior to the initiation offilling and capping activity, the bulk solution is filtered throughanother filter, e.g., another 0.2p pre-sterilized capsule or cartridgefilter, e.g., a polyethersulfone (PES) capsule filter.

In aspects, pre-integrity filter testing is performed using anindustry-accepted standard integrity test, such as, e.g., a water bubblepoint test, against the filter manufacturer's specification. In aspects,an acceptable result is a pressure of not less than about 46 psi under afiltration pressure limit of about 0.8 kg/cm² to about 1.8 kg/cm². Uponpassing the integrity test, in aspects the filter is then connected tothe filling line through a pre-sterilized vessel, e.g., buffer tank.

In aspects, prior to the initiation of filtration activity, thefilter/filtration unit is flushed with a sufficient volume of water toflush the filter, such as, e.g., about 200-about 250 mL of bulksolution, such as, e.g., about 180 mL, about 190 mL, about 200 mL, about210 mL, about 220 mL, or, e.g., about 230 mL of the bulk solution. Inaspects, the bulk solution is held within the filtration unit for aperiod of time during flushing, such as about 1.5 minutes, about 2minutes, about 2.5 minutes, or, e.g., about 3 minutes, during thisflushing process. In aspects, the flush and is then discarded. Inaspects, the flushing process is repeated a number of times, such as atleast one more time, at least two more times, at least 3 more times, atleast four more times, or, e.g., at least five more times. In aspects,the flushing process is performed at least two additional times for atotal of at least about 3 flushes, with the bulk solution used forflushing discarded after each flush.

In aspects, after discarding the filter flush solution, the entirequantity of remaining bulk solution is filtered into the sterile vessel,e.g., the sterile buffer tank.

In aspects, upon completing the filtration, the filling activity is theninitiated. In aspects, upon the completion of the filling activity, apost-filtration integrity test of the filter is performed using anindustry standard integrity test, such as, e.g., a water bubble pointtest. In aspects, an acceptable result is a pressure of not less thanabout 39.2 psi under a filtration pressure limit of about 0.8 kg/cm² toabout 1.8 kg/cm².

In aspects, the final step of a method of manufacturing composition(s)described herein is the process of filling and capping thecomposition(s).

In aspects, suitable sterile containers, such as, e.g., sterile vials,bottles such as, e.g., dropper bottles, are each filled to a target fillvolume. In aspects, single-dose bottles can be used. In aspects,multi-dose bottles can be used. In aspects, suitable containers areAbak® or Comod® bottles, or, e.g., similar or equivalent packaging,e.g., other bottles allowing compositions contained therein to beprovided as drops administered over several days. In aspects, a suitablesingle-dose or multi-dose container is made of EP-quality LDPE. Inaspects, a suitable single-dose or multi-dose container contains noadditives. In aspects, an exemplary filling volume is, e.g., a volume ofbetween about 1 mL and about 10 mL, such as a volume of between about 1mL and about 5 mL, or, e.g., a volume of between about 1 mL and about 3mL, such as a volume of about 2 mL to about 3 mL, e.g., a target volumeof about 2.6 mL to about 2.8 mL (about 2.62 g to about 2.82 g), such asabout 2.7 mL (about 2.72 g).

In aspects, after filling, the head space of each container is flushedwith nitrogen, e.g., filtered nitrogen. In aspects, a minimum nitrogenflow is established, such as, e.g., a minimum nitrogen flow of about 1.5L/min, about 2 L/min, about 2.5 L/min, or, e.g., about 3 L/min. Inaspects, this step comprises placing associated container (e.g., vial,bottle, etc.), such as the nozzle of the bottle, and capping the bottle.

In aspects, a first set of vials filled, e.g., the first about 20, about25, about 30, about 35, or, e.g., about 40 vials filled are collectedand identified as the initial system flush.

In aspects, checks for proper processing, e.g., proper filling volumeand vial sealing, are performed intermittently (e.g., at least 2 times,at least 5 times, at least 10 times, at least 20 times, at least 50times or more) during any single batch filling procedure. In aspects,the filling process is stopped, adjusted, or otherwise corrected iffilling processes do not meet previously defined standards (e.g., offill volume, air-tight sealing of vials, etc.). Packaged productidentified as not meeting predefined acceptance criteria are rejected.

According to some aspects, the invention provides a second method ofmanufacturing a composition described herein comprising the followingsteps.

In aspects, a first (“filter number 1”) and a second (“filter number 2”)filter, e.g., 0.2 μm capsule filter, are each integrity-tested using anindustry standard filter integrity test, e.g., a water bubble pointtest, against the filter manufacturer's specification(s). In aspects, anacceptable result of each test is a pressure of not less than about 46.0psi under a filtration pressure limit of about 0.8 kg/cm² to about 1.8kg/cm². In aspects, upon completion of integrity testing, filters areflushed with a sufficient amount of nitrogen to remove any residualwater from the filter pores.

In aspects, upon passing the integrity test, the outlet of filter number2 is connected to the inlet of filter number 1 using a suitableconnection mechanism, such as tubing, e.g., Pharma 50 silicone tubing,of a suitable length. Such length can be any suitable length for themanufacturing configuration, such as, e.g., a length of about 40 cm,about 50 cm, about 60 cm, about 70 cm, or about 80 cm. In aspects, theoutlet of filter number 1 is connected to a valve, e.g., a diaphragmvalve. In aspects, the inlet of filter number 2 is connected to asuitable connection mechanism, such as, e.g., tubing, for example Pharma50 silicone tubing, of suitable length for the manufacturingconfiguration, such as, for example, a length of about 1.5 meters, 2meters, 2.5 meters, 3 meters, or, e.g., about 3.5 meters, e.g., inaspects, about 2.30 meters. In aspects, the entire assembly issterilized using a suitable sterilization method, e.g., autoclaving.During sterilization, e.g., while autoclaving, in aspects, the diaphragmvalve is maintained in an open position. In aspects, upon completion ofsterilization, e.g., after autoclaving, the diaphragm valve is closedunder aseptic conditions. In aspects, the entire assembly is thenconnected to an empty manufacturing vessel (e.g., a “reactor vessel”).

In aspects, the manufacturing vessel/reactor vessel is sterilized with asufficient amount of water, e.g., water for injection (WFI), such as,e.g., about 100 Kg, about 110 Kg, about 120 Kg, about 130 Kg, about 140Kg, or, e.g., about 150 Kg of WFI. In aspects, this establishes asterilized “reactor vessel” or “SIP vessel”.

In aspects, a sufficient amount of WFI, e.g., about 120 Kg of WFI, at atemperature of not less than about 70° C., e.g., a temperature of about70° C.-about 80° C., is collected in a manufacturing vessel, such as,e.g., a stainless-steel (SS) manufacturing vessel.

In aspects, the WFI is cooled, for example to a temperature of about 20°C.-about 25° C., such as, e.g., by circulating the water through a waterjacket. In aspect, while cooling, e.g., simultaneously with cooling,nitrogen, e.g., 0.2μ-filtered nitrogen, is passed (e.g., bubbled)through the WFI, with all WFI collected in the manufacturing vessel.

In aspects, the dissolved oxygen content of the WFI is tested one ormore times, e.g., the WFI is routinely tested, to ensure that the WFIreaches a dissolved oxygen content of no more than about 2 ppm, e.g., nomore than about 1.5 ppm, no more than about 1 ppm, or, e.g., no morethan about 0.5 ppm.

In aspects, nitrogen bubbling is continued throughout the manufacturingprocess of one or more solutions of the method.

After completion of empty reactor sterilization, about 50 Kg, e.g.,about 50 Kg to about 70 Kg, of the about 120 Kg of WFI is transferred toa second manufacturing vessel, e.g., a stainless-steel manufacturingvessel. In aspects, this reserved WFI is used for one or more steps ofthe method, such as, e.g., used in the preparation of a drug phase,bringing composition(s) up to volume, or both, as is described furtherbelow.

In aspects, the establishment of a polymer phase is a first step(s) ofthe method of manufacturing.

In aspects, while maintaining the temperature of the remaining about 70Kg (e.g., about 50 to about 70 Kg) of WFI in the reactor vessel at about70° C. to about 80° C., such as about 73° C. to about 78° C., a suitablestirrer (mixer) is established in the reactor vessel. In aspects, thesuitable stirrer can be any stirrer suitable for the manufacturingconfiguration. In aspects, the stirrer/mixer is set to a stirrer speedof about 50 rpm to about 200 rpm, such as, e.g., about 75 rpm to about175 rpm, or, e.g., about 100-about 150 rpm. In aspects, the mixing speedcan be adjusted as necessary based on/according to the equipment beingused in the manufacturing process, the batch volume, etc., e.g.,according to the vessel geometry and the stirring dynamics duringmanufacture of the batch.

In aspects, the required quantity of a viscosity enhancer component,e.g., a gelling agent, e.g., gellan gum NF (national formulary), isadded to the reactor vessel. In aspects, stirring is maintained at asufficient speed, e.g., about 125 rpm±about 50 rpm, for a sufficienttime, e.g., for at least about 30 minutes, such as about 60 mins, or fora sufficient time to ensure complete dissolution of the gellan gum. Inaspects, the solution is maintained at a temperature of between about70° C. and about 80° C., such as, e.g., 73° C. and about 78° C., duringcontinuous stirring.

In aspects, the total required quantity of a preservative component,e.g., benzalkonium chloride, is added. In aspects, the resultingcomposition is mixed for a sufficient period of time to ensure that thepreservative component constituent(s) are completely dissolved.

In aspects, after complete dissolution of all previously addedingredients, the solution is cooled to a temperature of between about20° C. and about 25° C. In aspects, cooling is conducted under constantstirring. In aspects, this establishes the “polymer phase.”

In aspects, the polymer phase is sterilized at set temperature, such as,e.g., a temperature of about 122.0° C., or a period of time, e.g., forat least about 20 minutes. In aspects, constant stirring continuesduring this period, e.g., at a suitable speed, such as a speed of about125 rpm±about 50 rpm.

In aspects, upon completion of sterilization, the polymer phase iscooled, such as, e.g., to a temperature of about 20° C. to about 30° C.,e.g., 25° C. In aspects, while cooling, when the temperature of thepolymer phase reaches a set temperature, such as, e.g., a temperature ofabout 50° C. to about 70° C., such as, e.g., about 60° C., the stirringspeed is increased to a suitable increased mixing speed, e.g., astirring speed of about 250 rpm±50 rpm.

In aspects, the method of manufacturing continues with a second step(s)of preparing a drug phase solution.

In aspects, an amount of reserved WFI, e.g., about 50 kg of thereserved, cooled WFI, is collected in a suitable manufacturing vessel.In aspects, a suitable stirrer/mixer is established in the manufacturingvessel. In aspects, the mixer is set to a suitable stirring speed forthe manufacturing configuration being used, e.g., a stirring speed of,e.g., about 200 rpm to about 400 rpm, such as, e.g., about 250 rpm toabout 350 rpm. In aspects, the mixing speed can be adjusted as necessarybased on/according to the equipment being used in the manufacturingprocess, the batch size being manufactured, or both, e.g., according tothe vessel geometry and the stirring dynamics during the manufacture ofthe batch.

In aspects, the total quantity of solubilizing component, penetrationenhancer component, or compound(s) providing both solubilization andpenetration enhancement effect, e.g., polysorbate 80, tocopherolpolyethylene glycol succinate (TPGS), polyoxyl castor oil (e.g.,polyethoxylated castor oil, such as polyoxyl 35 castor oil), or, e.g.,protein/peptide enhancers (e.g., poly-arginine or polyserine) isoptionally added to the manufacturing vessel. In aspects, in certainformulations, such one or more ingredients is absent from thecomposition (e.g., is/are not added). The container(s) used to add eachingredient is/are rinsed multiple times, e.g., about 5 times, withapproximately 50 mL of WFI each time. The rinses are added to themanufacturing vessel under stirring. Stirring is continuous from thebeginning of the process to the end of the process, unless otherwiseindicated.

In aspects, the total required quantity of PAC, e.g., bimatoprostcompound(s), e.g., bimatoprost base, is added to the manufacturingvessel. The container(s) used to add the PAC constituent(s) is/arerinsed multiple times, e.g., about 2, about 3, about 4, or, e.g., about5 times, with approximately 25 mL of WFI each time. The rinses are addedto the manufacturing vessel. Stirring is continued for at least about 15minutes, such as at least about 30 minutes, at least about 45 minutes,at least about 60 minutes, or at least about 65 minutes, or for asufficient time to ensure complete dissolution of the PAC constituent(s)and composition uniformity.

In aspects, the total required quantity of BBC, e.g., timololcompound(s), e.g., salt(s) of timolol, e.g., timolol maleate, is addedto the manufacturing vessel. The container(s) used to add the BBCconstituent(s) is/are rinsed multiple times, e.g., about 2, about 3,about 4, or, e.g., about 5 times, with approximately 25 mL of WFI eachtime. The rinses are added to the manufacturing vessel. Stirring iscontinued for at least about 15 minutes, such as at least about 30minutes, at least about 45 minutes, at least about 60 minutes, or atleast about 65 minutes, or for a sufficient time to ensure completedissolution of the BBC constituent(s) and composition uniformity.

In aspects, upon the complete dissolution of all previously addedingredients, the total required quantity of a tonicity component, e.g.,mannitol, is added to the solution. In aspects, the resultingcomposition is mixed for a suitable period of time to allow the tonicitycomponent, e.g., mannitol, to completely dissolve.

Upon the complete dissolution of the mannitol, the total requiredquantity of a second solubilizer (if, e.g., a prior solubilizer wasoptionally added), e.g., a solubilizer which in aspects may also becharacterizable as a penetration enhancer, e.g., tromethamine, is addedto the solution. In aspects, the resulting composition is mixed for asufficient period of time to ensure complete dissolution of thecomponent, e.g., tromethamine. In aspects, such a period of time can be,e.g., at least about 5 minutes, at least about 10 minutes, at leastabout 15 minutes, or, e.g., at least about 20 min.

In aspects, the composition is then checked for clarity. In aspects,clarity is evaluated using visual inspection. In aspects,stirring/mixing is continued until visual clarity of the solution isachieved.

In aspects, the volume of the composition is then brought to betweenabout 50 L and about 60 L, e.g., to about 55 L (if, e.g., an exemplarybatch size of about 100 L is being manufactured; it should be understoodthat this and other steps of the methods of manufacturing described herecan be adjusted as needed for the batch size being manufactured) using,e.g., previously reserved WFI. In aspects, the composition is thenstirred for a sufficient period of time to ensure compositionuniformity, such as for at least about 5 minutes, at least about 10minutes, at least about 15 minutes, at least about 20 minutes, at leastabout 25 minutes, or, e.g., at least about 30 minutes. In aspects, thisestablishes the “drug phase”.

In aspects, an industry standard sampling protocol is used to sample andtest the drug phase to ensure that the phase meets pre-establishedspecification(s). Upon acceptance, in aspects, the drug phase istransferred to the sterilized polymer phase via aseptic filtration (seebelow).

In aspects, the method of manufacture/manufacturing comprises or nextcomprises a step of aseptic filtration. As has been previously stated,references to order of operation, e.g., “next” as used here, should notbe interpreted as limiting. In aspects, manufacturing steps/processesdescribed can be performed in any suitable order provided the resultingcomposition comprises the characteristic(s) described herein.

In aspects, aseptic filtration of the drug phase into the sterilepolymer phase is performed at a filtration pressure of, e.g., about 0.8Kg/cm²-about 1.8 Kg/cm².

In aspects, prior to beginning the aseptic filtration, the weight of thedrug phase is noted. In aspects, an amount of drug phase, e.g., about 50Kg to˜60 Kg, e.g., about 55 Kg of the drug phase (which can be referredto as the “concentrated drug phase”), is filtered into the reactorvessel containing the polymer phase through 2 sterilized 0.2 μm filtersconnected in series.

In aspects, WFI is passed through the filters a number of times, such asabout two times or about three times with, e.g., between about 2 L andabout 3 L of WFI used each time, such as, e.g., about 2.5 L of WFI eachtime. In aspects, the filtrate added to the reactor vessel each time toensure all required drug phase is added into the reactor vessel. Inaspects, the resulting composition is then stirred for a sufficientperiod of time and at a suitable speed to ensure composition uniformity.In aspects for example, the composition is mixed for at least about 45minutes, at least about 50 minutes, at least about 55 minutes, at leastabout 60 minutes, at least about 65 minutes, at least about 75 minutes,at least about 80 minutes, or, e.g., at least about 85 minutes, such as,e.g., about 1 hour, at a suitable speed, such as, e.g., a speed of about150 rpm-about 350 rpm, or, e.g., a speed of about 200 rpm to about 300rpm, to ensure composition uniformity.

In aspects, a post-filtration integrity test of the filter is performedusing an industry standard filter integrity test, e.g., a water bubblepoint test. In aspects, an acceptable result is a pressure of not lessthan about 34.8 psi under a filtration pressure limit of about 0.8kg/cm² to about 1.8 kg/cm².

In aspects, the composition is pH adjusted using one or more pHadjusting agents. In aspects, pH of the solution is adjusted by theaddition or one or more pH adjusting agents, with the solutionsufficiently mixed after each addition such that the composition has auniform pH prior to (1) sampling for pH, and (2) applying further pHadjustment as needed. In aspects, pH is adjusted to a pH of 6-about 7.5,such as, e.g., about 6.1-about 7.2, e.g., about 6.2 to about 7 using thepH adjusting agent(s).

In aspects, the method of manufacturing further comprises a finalcombined composition (bulk solution) filtration step.

In aspects, filtration of the final combined composition (bulk solution)is then performed using a suitable filter, e.g., such as an 8 μm filter,such as, e.g., an 8 μm PP2 MidiCap® filter (Sartorius).

In aspects, prior to initiating filtration activity, a sterilizedfilter, e.g., a sterilized 8.0 μm filter, e.g. a sterilized 8 μmpolypropylene filter, is flushed with a sufficient amount of bulksolution, such as, e.g., about 80 mL to about 140 mL of bulk solution,e.g., about 100 mL to about 120 mL of bulk solution, a number of timessuch as about 2 times, about 3 times, about 4 times, or, e.g., about 5times. In aspects, during each flush, the composition is held in thefiltration unit for an extended period of time, such as about 1 minute,about 2 minutes, about 3 minutes, about 4 minutes, or, e.g., about 5minutes, prior to discarding each flush. In aspects, upon completion ofthe flushing process, filtration of the bulk solution is performed. Inaspects, the filtrate collected in a sterile receiving vessel.

In aspects, a final step of the method is filling and capping step(s).

In aspects, suitable sterile containers, such as, e.g., sterile vials,bottles such as, e.g., dropper bottles, are each filled to a target fillvolume. In aspects, single-dose bottles can be used. In aspects,multi-dose bottles can be used. In aspects, suitable containers areAbak® or Comod® bottles, or, e.g., other bottles allowing compositionscontained therein to be provided as drops administered over severaldays. In aspects, a suitable single-dose or multi-dose container is madeof EP-quality LDPE. In aspects, a suitable single-dose or multi-dosecontainer contains no additives. In aspects, an exemplary filling volumeis, e.g., a volume of between about 1 mL and about 10 mL, such as avolume of between about 1 mL and about 5 mL, or, e.g., a volume ofbetween about 1 mL and about 3 mL, such as a volume of about 2 mL toabout 3 mL, e.g., a target volume of about 2.6 mL to about 2.8 mL (about2.62 g to about 2.82 g), such as about 2.7 mL (about 2.72 g).

In aspects, after filling, the head space of each container is flushedwith nitrogen, e.g., filtered nitrogen. In aspects, a minimum nitrogenflow is established, such as, e.g., a minimum nitrogen flow of about 1.5L/min, about 2 L/min, about 2.5 L/min, or, e.g., about 3 L/min. Inaspects, this step comprises placing associated container (e.g., vial,bottle, etc.), such as the nozzle of the bottle, and capping the bottle.

In aspects, a first set of vials filled, e.g., the first about 20, about25, about 30, about 35, or, e.g., about 40 vials filled are collectedand identified as the initial system flush.

In aspects, checks for proper processing, e.g., proper filling volumeand vial sealing, are performed intermittently (e.g., at least 2 times,at least 5 times, at least 10 times, at least 20 times, at least 50times or more) during any single batch filling procedure. In aspects,the filling process is stopped, adjusted, or otherwise corrected iffilling processes do not meet previously defined standards (e.g., offill volume, air-tight sealing of vials, etc.). Packaged productidentified as not meeting predefined acceptance criteria are rejected.

Product-by-Process Aspects

In aspects, the invention provides compositions comprising (1) a PAC,e.g., bimatoprost, e.g., bimatoprost base in an amount of, for example,about 0.005% w/v-about 0.02% w/v or other amount(s) disclosed herein;(2) a BBC, e.g., a timolol compound, e.g., a salt of timolol, e.g.,timolol maleate, in an amount of, for example, about 0.4% w/v-about 0.8%w/v or other amount(s) disclosed herein; (3) a quaternary ammonium salt,e.g., benzalkonium chloride, in an amount of, for example, about 0.003%w/v-about 0.005% w/v or other amount(s) disclosed herein; (4) apenetration enhancer component, e.g., polysorbate 80, TPGS, cremophorEL, or one or more other penetration enhancer component constituentsdisclosed herein in an amount of, for example, about 0.25% w/v-about2.5% w/v; (5) a tonicity agent, e.g., sodium chloride, in an amount of,for example, about 0.05% w/v-about 1.5% w/v or other amount(s) disclosedherein; (6) a buffer component comprising one or more bufferconstituents, such as, e.g., a phosphate buffer, a citrate buffer, orboth, in an amount of, for example, about 0.015% w/v-about 0.6% w/v orother amount(s) disclosed herein, and (7) a sufficient amount of pHadjusting agent(s) to establish the pH of the composition at about6-about 8, such as, e.g., about 6.9-about 7.5, e.g., about 7.1-about7.3, and water, the composition made by a process comprising (1)preparing a bulk composition, (2) offline filtering the bulkcomposition, (3) online filtering the bulk composition, and (4)packaging of the final composition, wherein the process is either anaseptic process or a non-aseptic process. In aspects, such compositionscan be manufactured by a process comprising any one or moremanufacturing steps described in the “Methods of Manufacturing” sectionherein. In aspects, compositions can lack one or more of theconstituents described above (e.g., in this paragraph). In aspects, acomposition resulting from such process(es) maintains its established pHwithin acceptable limits (e.g., about 6 to about 8, e.g., about6.2-about 7 or about 6.9-about 7.5, according to its established pHduring its manufacture). In aspects, a composition resulting from suchprocess(es) retains at least about 95%, such as, e.g., at least about97%, about 98%, or, e.g., at least about 99% of the original PAC, BBC,or both when stored at about 25° C. +/−2° C. and about 40% +/−5%relative humidity; about 40° C. +/−2° C. and not more than about 25%relative humidity; about 15° C.-about 27° C. and about 60% relativehumidity; about 38° C.-about 42° C. and 75% relative humidity; or whenstored under any such condition, or a sequential combination of suchconditions. In aspects, a composition resulting from such process(es)comprises less than about 2.5% total impurities, e.g., less than about2%, less than about 1.5%, less than about 1%, or, e.g., less than about0.5% total impurities after storage at about 25° C. +/−2° C. and about40% +/−5% relative humidity; about 40° C. +/−2° C. and not more thanabout 25% relative humidity; about 15° C.-about 27° C. and about 60%relative humidity; about 38° C.-about 42° C. and 75% relative humidity;or when stored under any such condition, or a sequential combination ofsuch conditions. In aspects, a composition resulting from suchprocess(es) comprises or maintains any one or more such feature(s)described in this paragraph for a period of at least about 1 month, suchas, e.g., ≥˜3 months, ≥˜6 months, ≥˜9 months, ≥˜12 months, ≥˜14 months,≥˜16 months, ≥˜18 months, ≥˜20 months, ≥˜22 months, ≥˜24 months, ≥˜26months, ≥˜28 months, ≥˜30 months, ≥˜32 months, ≥˜34 months, or, e.g.,≥˜36 months.

In aspects, the invention provides compositions comprising (1) a PAC,e.g., bimatoprost, e.g., bimatoprost base in an amount of, for example,about 0.005% w/v-about 0.02% w/v or other amount(s) disclosed herein;(2) a BBC, e.g., a timolol compound, e.g., a salt of timolol, e.g.,timolol maleate, in an amount of, for example, about 0.4% w/v-about 0.8%w/v or other amount(s) disclosed herein; (3) a quaternary ammonium salt,e.g., benzalkonium chloride, in an amount of, for example, about 0.003%w/v-about 0.005% w/v or other amount(s) disclosed herein; (4) optionallya penetration enhancer component, e.g., polysorbate 80, TPGS, cremophorEL, or one or more other penetration enhancer component constituentsdisclosed herein in an amount of, for example, about 0.25% w/v-about2.5% w/v; (5) a solubilizing component, e.g., tromethamine, in an amountof, for example, about 0.05% w/v-about 1% w/v or other amount(s)disclosed herein; (6) a viscosity enhancer component, e.g., gellan gum,in an amount of, for example, about 0.1% w/v-about 1% w/v or otheramount(s) disclosed herein; (7) a tonicity agent, e.g., mannitol, in anamount of, for example, about 2% w/v-about 6% w/v or other amount(s)disclosed herein; (8) a buffer component comprising one or more bufferconstituents, such as, e.g., a phosphate buffer, a citrate buffer, orboth, in an amount of, for example, about 0.015% w/v-about 0.6% w/v orother amount(s) disclosed herein, and (9) a sufficient amount of pHadjusting agent(s) to establish the pH of the composition at about6-about 8, more specifically between about 6.1-about 7.5, or, e.g.,about 6.2-about 7, and water, the composition made by a processcomprising (1) preparing a polymer phase, (2) preparing a drug phase,(3) filtering the drug phase into the polymer phase, (4) filtering thecomposition resulting from (3), and (5) packaging the final composition,wherein the process is either an aseptic process or a non-asepticprocess. In aspects, such compositions can lack one or more of theconstituents described above. In aspects, the composition, e.g., thecomposition of this paragraph, maintains its established pH withinacceptable limits (e.g., about 6.2-about 7, according to its establishedpH during its manufacture); retains at least about 95%, such as, e.g.,at least about 97%, about 98%, or, e.g., at least about 99% of theoriginal PAC, BBC, or both when stored at about 25° C. +/−2° C. andabout 40% +/−5% relative humidity; about 40° C. +/−2° C. and not morethan about 25% relative humidity; about 15° C.-about 27° C. and about60% relative humidity; about 38° C.-about 42° C. and 75% relativehumidity; or when stored under any such condition, or a sequentialcombination of such conditions; comprises less than about 2.5% totalimpurities, e.g., less than about 2%, less than about 1.5%, less thanabout 1%, or, e.g., less than about 0.5% total impurities after storageat about 25° C. +/−2° C. and about 40% +/−5% relative humidity; about40° C. +/−2° C. and not more than about 25% relative humidity; about 15°C.-about 27° C. and about 60% relative humidity; about 38° C.-about 42°C. and 75% relative humidity; or when stored under any such condition,or a sequential combination of such conditions; or any combination of orall of such characteristic(s) for a period of at least about 1 month,such as, e.g., ≥˜3 months, ≥˜6 months, ≥˜9 months, ≥˜12 months, ≥˜14months, ≥˜16 months, ≥˜18 months, ≥˜20 months, ≥˜22 months, ≥˜24 months,≥˜26 months, ≥˜28 months, ≥˜30 months, ≥˜32 months, ≥˜34 months, or,e.g., ≥˜36 months.

In one aspect, the invention provides a pharmaceutically acceptable andophthalmologically suitable composition comprising bimatoprost in anamount of about 0.005% to about 0.02% by weight and timolol in an amountof about 0.25% to about 0.5% by weight, benzalkonium chloride in anamount of about 0.003% to about 0.007% by weight, and/or a penetrationenhancer other than benzalkonium chloride, wherein the compositions arecapable of reducing intraocular pressure in a mammalian eye sufferingfrom increased intraocular pressure and are further capable ofmaintaining the stability of drug when stored up to at least 3 months at40° C. and 75% relative humidity, at 25° C. and 60% relative humidity,or under either condition, or a sequential combination of suchconditions, made by a process comprising one or more heat sterilizationsteps, gas sterilization steps, filtration sterilization steps,radiation sterilization steps, or any combination thereof.

Packaging/Delivered Form and Kits

In aspects, compositions provided by the invention can be provided with,e.g., contained within, a delivery device suitable for administering thecomposition. In aspects, such a delivery device can be any suitabledelivery device capable of maintaining the compositions therein insterile form prior to administration. In aspects, such a delivery devicecan be capable of preventing detectable or significant degradation ofthe compositions during shipping or storage. In aspects, compositionscan be provided with, e.g., contained within, dropper bottle(s), squeezebottle(s), vials, and the like which are commonly known in the art.

According to certain embodiments, pharmaceutically acceptable andophthalmologically suitable compositions provided by the invention canbe packaged in any suitable packaging, such suitability being at leastin part defined by protecting the compositions held therein fromdegradation, contamination, or both. In certain aspects, suitablepackaging materials are materials which exhibit less than about 20%,such as ≤˜18%, ≤˜16%, ≤˜14%, ≤˜12%, ≤˜10%, ≤˜8%, ≤˜6%, ≤˜4%, ≤˜2% oreven less sorption of a PAC constituent, such as, e.g., a bimatoprostcompound, or more specifically bimatoprost base, a BBC constituent, suchas, e.g., a timolol compound, or more specifically timolol maleate, orboth. In some respects, suitable materials include but may not belimited to packaging material made of select polyolefins, such as, e.g.,DuPont® 20 LDPE, Chevron 5502 HDPE, Atofina 3020 PP, polypropylenehomopolymers, low ethylene content (<8%) polypropylenes, and polymers(HDPE, PP) with low content of additives (<5%) and with low flexuralmodulus (<200 kpsi). In some respects, a suitable material is anEP-quality LDPE which, in further aspects, may contain no additives. Inaspects, suitable packaging can comprise a polypropylene containerprovided that that polypropylene container is not packaged in abag/container containing an iron oxide oxygen scavenger. In aspects,suitable packaging can be, e.g., single-dose or multi-dose bottles suchas, e.g., those identifiable in the art as Abak© or Comod© packaging,or, e.g., equivalent such bottles allowing the compositions to beapplied in the form of eye drops. In aspects, suitable packaging canallow the compositions to be applied in the form of eye drops over thecourse of several days, e.g., 2+ days or more, such as, e.g., more than7 days, ore more than 14 days or more, e.g., more than 21 days or morethan about 30 days. In aspects, suitable packaging provides forcompositions to be applied in the form of eye drops over the course ofseveral days without the presence of one or more preservatives. Inaspects, suitable packaging allows for compositions to remain stable,e.g., maintaining one or more characteristics of stability describedelsewhere herein, when stored at controlled room temperature (15° C. to25° C. +/−2° C.), when stored at about 25° C. +/−2° C. and about 40%+/−5% relative humidity; about 40° C. +/−2° C. and not more than about25% relative humidity; about 15° C.-about 27° C. and about 60% relativehumidity; about 38° C.-about 42° C. and 75% relative humidity; or whenstored under any such condition, or a sequential combination of suchconditions, for a period of at least about 1 month, such as, e.g., atleast about 1, ˜2, ˜4, ˜6, ˜8, ˜10, ˜12, ˜14, ˜16, ˜18, ˜20, ˜22, ˜24,˜26, ˜28, ˜30, ˜32, ˜34, or, e.g., ˜36 months or longer.

In certain aspects, the packaging can comprise or can be mostlycomprised of (e.g., comprise in an amount ≥˜10%, ≥˜20%, ≥˜30%, ≥˜40%, or≥˜50%, such as, e.g., comprise in an amount ≥˜60%, ≥˜70%, ≥˜80%, ≥˜90%or more) an ultraviolet-light blocking agent or material, e.g., amaterial comprising ultraviolet-light blocking agent(s). In aspects,such a material can be capable of blocking ≥˜1%, ≥˜5%, ≥˜10%, ≥˜20%,≥˜30%, ≥˜40%, or ≥˜50%, such as, e.g., ≥˜60%, ≥˜70%, ≥˜80%, ≥˜90% ormore of the ultraviolet light in the environment from entering thecontainer. In aspects, compositions described herein can be packaged in,stored, in, or both packaged and stored in a container wherein thecontainer significantly reduces exposure of the composition to UV Bradiation, such as by at least about 50%, at least about 65%, at leastabout 75%, at least about 90%, at least about 95%, or at least 99%. Insome aspects, the packaging material of a composition described hereinis semi- or completely opaque, while in alternative aspects, thepackaging is semi- or completely clear. In aspects, packaging cancomprise different parts wherein one component of the packagingcomprises a first material and one or more components of the packagingcontain a second (or more) material(s).

In certain aspects, packaging can be selected based on the method ofdelivery of the compositions herein (e.g., compositions provided as agel can be provided in suitable packaging for gels wherein compositionsprovided as a liquid can be provided in suitable packaging for liquids,e.g., in a user-friendly dropper bottle; in aspects, a composition ingel form can also or alternatively be provided in a dropper bottle fordrop-by-drop administration.) In aspects, the compositions of theinvention are stored in a packaging that facilitates the delivery of thecomposition as eye drops.

In one aspect, ophthalmic compositions provided by the inventioncomprise a bimatoprost compound, e.g., bimatoprost base, a timololcompound, e.g., timolol maleate, and one or more pharmaceuticallyacceptable excipient(s), and are provided in single-dose bottles. In analternative aspect, such compositions are provided in multi-dosebottles, such as multi-dose eye dropper bottles. In aspects, suchmulti-dose bottles allow for the composition, e.g., provided as asolution to be dropped into the recipient's eye(s), to be applied asliquid drops over a course of treatment, such as, e.g., over the courseof many days, several weeks, months, or longer.

In aspects, the average force required to release one or more drops ofthe compositions described herein from a dropper bottle (a standardbottle common in the art for dispensing liquid in droplet form), bycompressing the middle section of the storage body of such a dropperbottle, ranges between ˜1.7-˜2.8 Kg for release of the first drop, e.g.,˜1.7-˜2.6, ˜1.7-˜2.4, ˜1.7-˜2.2, or ˜1.7-˜2.0 Kg. In aspects, successivedrops can require more tension, such as can require an additional˜20-30% of force for release of the second drop, and, e.g., anadditional force of ˜24-˜50% for release of the third drop.

In aspects, compositions are provided in single-dose or multi-dosepackaging.

In aspects, a single-dose package comprises a single-dose of compositionwithin a single-dose administration container. In aspects, a multi-dosepackage comprises a plurality of single-dose administration containers.In aspects, a multi-dose package comprises a plurality of doses within asingle administration container. For example, a multi-dose package canbe, e.g., a single dropper bottle comprising sufficient volume ofcomposition to administer the composition multiple times over the courseof an administration period, such as (but certainly not limited to)administration of about 1-3×/day over a period of about 1-7 days, ˜1week-˜1 month, ˜1 month-˜3 months, ˜3 months-˜6 months, or, e.g., ˜6months-˜1 year.

In aspects, packaging of compositions is any suitable packaging whicheffectively provides compositions with a shelf life of at least about 1month, such as, e.g., ≥˜3 weeks, ≥˜4 weeks (1 month), ≥˜5 weeks, ≥˜6weeks, ≥˜7 weeks, ≥˜8 weeks (2 months), ≥˜9 weeks, ≥˜10 weeks, ≥˜11weeks, ≥˜12 weeks (3 months), ≥˜13 weeks, ≥˜14 weeks, ≥˜15 weeks, ≥˜16weeks (4 months), or more, such as ≥˜5 months, ≥˜6 months, ≥˜7 months,≥˜8 months, ≥˜9 months, ≥˜10 months, ≥˜11 months, or ≥˜12 months (1year), or even longer, such as, ≥˜18 months, ≥˜24 months (2 years), ≥˜30months, or, e.g., ≥˜36 months (3 years) or longer. The term “shelf life”has been described elsewhere herein. In aspects, shelf life refers to aperiod of time wherein any API of the composition loses more than about10%, such as, e.g., ≤˜9%, ≤˜8%, ≤˜7%, ≤˜6%, ≤˜5%, ≤˜4%, ≤˜3%, ≤˜2%, or,e.g., ≤˜1%, of the potency while in storage after manufacturing andprior to use.

Kits (Collections of Compositions and Administration Devices)

In aspects, the invention provides kits comprising one or morebimatoprost and timolol compound compositions described herein and oneor more delivery devices for such compounds. In aspects, a kit providedby the invention can comprise a single delivery device comprising asingle composition, the composition present in an amount representativeof a single dose. In aspects, a kit provided by the invention cancomprise a single delivery device comprising a single composition, thecomposition present in an amount representative of multiple doses, e.g.,2 or more, 3 or more, 5 or more, 10 or more 20 or more, 30 or more, or,e.g., 50 or more doses. In aspects, a kit provided by the invention cancomprise a plurality of delivery devices comprising a singlecomposition, the composition present in an amount representative of asingle dose. In aspects, a kit provided by the invention can comprise aplurality of delivery devices comprising a single composition, thecomposition present in an amount representative of a multiple doses,e.g., 2 or more, 3 or more, 5 or more, 10 or more 20 or more, 30 ormore, or, e.g., 50 or more doses. In aspects, a kit provided by theinvention can comprise multiple compositions in multiple deliverydevices, wherein at least one ingredient of at least one compositionvaries from that of at least one other composition in either presence oramount. In aspects, a kit provided by the invention can comprisemultiple compositions in multiple delivery devices, wherein the amountof at least one composition in one delivery device varies from theamount of at least one other composition in at least one other deliverydevice. In aspects, a dose can be a single drop. In aspects, a dose canbe 2 drops. In aspects, a dose can be 3 drops. Typically, a dose is oneor two drops, e.g., a single drop.

In aspects, the invention provides a kit wherein compositions arepre-filled in a delivery device, and a kit comprises one or morepre-filled delivery devices and one or more additional components tofacilitate administration of the composition(s). For example, inaspects, the invention provides a kit wherein composition(s) areprovided in one or more pre-filled containers which facilitateadministration of the compositions by drops, such as, e.g., one or morepre-filled dropper bottles as described herein.

In aspects, the invention provides for a kit as described in thissection, wherein the kit has a shelf life when stored at about roomtemperature, such as, e.g., about 25° C. +/−˜2° C., for at least about 1month, e.g., ˜2, ˜3, ˜4, ˜5, or at least ˜6 months (e.g., 6-36 months).

Stored at Room Temperature

In aspects, compositions provided by the invention, e.g., compositionsin final packaged form, such as, e.g., compositions provided as acomponent of a kit, are stable when stored at standard room temperature,that is, controlled room temperature of about 15° C. to 27° C., e.g.,about 25° C. +/−2° C. for a period of at least about 1 month, e.g., ≥˜3,≥˜6, ≥˜9, ≥˜12, ≥˜18, ≥˜24, ≥˜28, ≥˜33, or, e.g., ≥˜36 months.

Representative Experiments/Embodiments (“Examples”)

The following detailed exemplary expository descriptions or experimentsinvolving embodiments, applications, or related principles, of orotherwise related to the invention (“Examples”) are provided to assistreaders in further understanding aspects of the invention or principlesrelated to the invention or practice of aspects of the invention.

Any particular materials, methods, steps, and conditionsemployed/described in the following Examples, and any results thereof,are merely intended to further illustrate aspects of the invention.These Examples reflect exemplary embodiments of the invention, and thespecific methods, findings, principles of such Examples, and the generalimplications thereof, can be combined with any other part of thisdisclosure. However, readers should understand that the invention is notlimited by these Examples or any part thereof.

Example 1

Table 3 below provides an exemplary formulation (Formulation A),providing a list of ingredients suitable for compositions of the presentinvention provided in the form of a solution.

TABLE 3 Exemplary Formulation A. Bimatoprost, Timolol, & PenetrationEnhancer (Solution). MATERIALS Qty./mL % w/v Bimatoprost 0.05-0.2 mg0.005-0.02 Timolol Maleate (equiv. to timolol) 4-8 mg  0.4-0.8 (2.9-5.9mg) Solubilizers and penetration 2.5-25 mg 0.25-2.5 enhancers (such asPS-80, TPGS, Cremophor EL, etc.) Benzalkonium chloride NF (added0.03-0.07 mg  0.003-0.007 as 10% w/v solution) Sodium chloride USP0.5-15 mg 0.05-1.5 Dibasic sodium phosphate USP 0.1-5 mg 0.01-0.5(Heptahydrate) Citric acid monohydrate USP 0.05 mg-0.9 mg 0.005-0.09Sodium hydroxide NF q.s. to adjust pH q.s. to adjust 7.1 to 7.3 pH 7.1to 7.3 Hydrochloric acid NF q.s. to adjust pH q.s. to adjust 7.1 to 7.3pH 7.1 to 7.3 Water for Injection USP q.s. to 1 mL q.s. to 1 mL

Table 4 below provides an exemplary composition (Composition A),providing a list of ingredients in exemplary amounts according toFormulation A, suitable for compositions of the present inventionprovided in the form of a solution.

TABLE 4 Exemplary Composition A. Bimatoprost, Timolol, & PenetrationEnhancer (Solution). MATERIALS Qty./mL % Bimatoprost 0.10 mg 0.01Timolol Maleate (equiv. to timolol) 6.8 mg 0.68 (5.0 mg) Solubilizersand penetration enhancers 10.0 mg 1 (such as PS-80, TPGS, Cremophor EL,etc.) Benzalkonium chloride NF (added as 0.05 mg 0.005 10% w/v solution)Sodium chloride USP 8.0 mg 0.8 Dibasic sodium phosphate USP 2.68 mg0.268 (Heptahydrate) Citric acid monohydrate USP 0.14 mg 0.014 Sodiumhydroxide NF q.s. to adjust q.s. to adjust pH 7.1 to 7.3 pH 7.1 to 7.3Hydrochloric acid NF q.s. to adjust q.s. to adjust pH 7.1 to 7.3 pH 7.1to 7.3 Water for Injection USP q.s. to 1 mL q.s. to 1 mL

Example 2

Table 5 below provides two exemplary formulations (Formulation B andFormulation C), providing a list of ingredients suitable forcompositions of the present invention provided in the form of a gel.

TABLE 5 Exemplary Formulation B and Formulation C. Bimatoprost & Timololwith and without Penetration Enhancer (Gel). MATERIALS Qty./mL % Qty./mL% Bimatoprost 0.05-0.2 mg 0.005-0.02  0.05-0.2 mg 0.005-0.02  TimololMaleate (equiv. to 4-8 mg 0.4-0.8 4-8 mg 0.4-0.8 timolol) (2.9-5.9 mg)(2.9-5.9 mg) Solubilizers and penetration — — 2.5-25 mg 0.25-2.5 enhancers (such as PS-80, TPGS, Cremophor EL, etc.) Tromethamine 0.5-10mg 0.05-1   0.5-10 mg 0.05-1   Benzalkonium chloride NF 0.03-0.07 mg0.003-0.007 0.03-0.07 mg 0.003-0.007 (added as 10% w/v solution)Mannitol 20-60 mg 2-6 20-60 mg 2-6 Gellan Gum 1-10 mg 0.1-1   1-10 mg0.1-1   Sodium hydroxide NF q.s. to adjust q.s. to adjust q.s. to adjustq.s. to adjust pH 6.2 to 7 pH 6.2 to 7 pH 6.2 to 7 pH 6.2 to 7Hydrochloric acid NF q.s. to adjust q.s. to adjust q.s. to adjust q.s.to adjust pH 6.2 to 7 pH 6.2 to 7 pH 6.2 to 7 pH 6.2 to 7 Water forInjection USP q.s. to 1 mL q.s. to 1 mL q.s. to 1 mL q.s. to 1 mL

Table 6 below provides two exemplary compositions (Composition B andComposition C), providing a list of ingredients in exemplary amountsaccording to Formulations B and Formulation C, suitable for compositionsof the present invention provided in the form of gel.

TABLE 6 Exemplary Composition B and Composition C. Bimatoprost & Timololwith and without Penetration Enhancer (Gel). Bimatoprost + Bimatoprost +Timolol Timolol (no penetration (with penetration enhancer) enhancer)MATERIALS Qty./mL % Qty./mL % Bimatoprost 0.10 mg 0.01 0.10 mg 0.01Timolol Maleate 6.8 mg 0.068 6.8 mg 0.68 (equiv. to timolol) (5.0 mg)(5.0 mg) Solubilizers and — — 10.0 mg 1 penetration enhancers (such asPS-80, TPGS, Cremophor EL, etc.) Tromethamine 1.85 mg 0.185 1.85 mg0.185 Benzalkonium 0.05 mg 0.005 0.05 mg 0.005 chloride NF (added as 10%w/v solution) Mannitol 40.5 mg 4.05 40.5 mg 4.05 Gellan Gum 6.0 mg 0.66.0 mg 0.6 Sodium hydroxide q.s. to q.s. to q.s. to q.s. to NF adjust pHadjust pH adjust pH adjust pH 6.2 to 7 6.2 to 7 6.2 to 7 6.2 to 7Hydrochloric acid q.s. to q.s. to q.s. to q.s. to NF adjust pH adjust pHadjust pH adjust pH 6.2 to 7 6.2 to 7 6.2 to 7 6.2 to 7 Water forInjection q.s. to 1 q.s. to 1 q.s. to 1 q.s. to 1 USP mL mL mL mL

Example 3

The following manufacturing process can be used to manufacture acomposition according to Formulation A of Table 3, e.g., Composition A,of Table 4 (Example 1).

Part 1. Bulk Solution Manufacturing (100 L):

The manufacturing vessel/reactor vessel is sterilized with about 120 Kgof water for injection (WFI), accomplished by collection of about 120 Kgof WFI in the vessel at a temperature of at least about 70° C.

The WFI is cooled to about 20° C.-about 25° C., such as by circulatingthe water through a water jacket. While cooling, e.g., simultaneouslywith cooling, 0.2μ-filtered nitrogen is bubbled through the WFI, withall WFI collected in the manufacturing vessel.

The dissolved oxygen content of the WFI is routinely tested to ensurethat the WFI reaches a dissolved oxygen content of no more than 2 ppm.

Nitrogen bubbling is continued throughout bulk solution manufacturing.

About 70 Kg of WFI is transferred into a separate holding vessel. ThisWFI is used for rinsing, preparation of 0.1N hydrochloric acid (for pHadjustment), and preparation of 0.1N sodium hydroxide solution (for pHadjustment), and for bringing the final composition up to a target finalvolume.

A suitable stirrer is set to a speed of about 400 rpm±about 100 rpmwithin the manufacturing vessel containing about 50 Kg of WFI. Themixing speed is adjusted as necessary based on/according to theequipment and batch, e.g., vessel geometry and the stirring dynamics.

The total required quantity of benzalkonium chloride (BKC) solution isadded to the manufacturing vessel. The container used to add the BKC isrinsed multiple times, e.g., about 5 times, with approximately 50 mL ofWFI each time. The rinses are added to the manufacturing vessel.Stirring is continued for at least about 10 minutes, such as for about15 to 17 minutes, or for a sufficient time to ensure completedissolution and composition uniformity.

The total required quantity of solubilizer, penetration enhancer, orcompound(s) providing both solubilization and penetration enhancementeffect, e.g., polysorbate 80, tocopherol polyethylene glycol succinate(TPGS), polyoxyl castor oil (e.g., polyethoxylated castor oil, such aspolyoxyl 35 castor oil), or, e.g., protein/peptide enhancers (e.g.,poly-arginine or polyserine) is added to the manufacturing vessel. Thecontainer used to add the polysorbate 80 is rinsed multiple times, e.g.,about 5 times, with approximately 50 mL of WFI each time. The rinses areadded to the manufacturing vessel under stirring. Stirring is continuousfrom the beginning of the process to the end of the process, unlessotherwise indicated.

The total required quantity of bimatoprost compound is added to themanufacturing vessel. The container used to add the bimatoprost compoundis rinsed multiple times, e.g., about 3 times, with approximately 25 mLof WFI each time. The rinses are added to the manufacturing vessel.Stirring is continued for at least about 15 minutes, such as at leastabout 30 minutes, at least about 45 minutes, at least about 60 minutes,or at least about 65 minutes, or for a sufficient time to ensurecomplete dissolution of the bimatoprost compound and compositionuniformity.

The total required quantity of timolol compound is added to themanufacturing vessel. The container used to add the timolol compound isrinsed multiple times, e.g., about 3 times, with approximately 25 mL ofWFI each time. The rinses are added to the manufacturing vessel.Stirring is continued for at least about 15 minutes, such as at leastabout 30 minutes, at least about 45 minutes, at least about 60 minutes,or at least about 65 minutes, or for a sufficient time to ensurecomplete dissolution of the timolol compound and composition uniformity.

The volume of the composition in the manufacturing vessel is brought upto about 90 L (e.g., about 90 Kg) using previously reserved WFI. Theresulting solution is stirred for at least about 15 minutes, such as atleast about 20 minutes, at least about 25 minutes, at least about 30minutes, or, e.g., at least about 35 minutes or for a sufficient time toensure composition uniformity.

The total required quantity of a first buffer, e.g., dibasic sodiumphosphate (heptahydrate), is added to the manufacturing vessel. Stirringis continued for at least about 5 minutes, such as at least about 10minutes or at least about 15 minutes, or for a sufficient time to ensurecomplete dissolution of the buffer component/ingredient and compositionuniformity. Composition uniformity is ensured by inspecting for visualclarity of the solution.

The total required quantity of a second buffer, e.g., citric acidmonohydrate, is added to the manufacturing vessel. Stirring is continuedfor at least about 5 minutes, such as at least about 10 minutes or atleast about 15 minutes, or for a sufficient time to ensure completedissolution of the buffer component/ingredient and compositionuniformity. Composition uniformity can be ensured by inspecting forvisual clarity of the solution.

The total required quantity of sodium chloride (e.g., sodium chlorideUSP) is added to the manufacturing vessel and stirring is continued toensure its complete dissolution. Composition uniformity can be ensuredby inspecting for visual clarity of the solution.

The pH of the bulk solution is checked. If required, the pH of the bulksolution is adjusted to about 7.2 (e.g., to a pH within a range limitedto about 6.9-about 7.5, such as, e.g., about 7.1-about 7.3, e.g., about7.2) using 0.1N sodium hydroxide solution or 0.1N hydrochloric acidsolution. The bulk solution is mixed for at least about 3 minutes, suchas at least about 5 minutes, at least about 10 minutes, or for asufficient amount of time to ensure uniformity of the solution aftereach addition of sodium hydroxide or hydrochloric acid before measuringor repeating the measurement of the pH during pH adjustment.

The final volume of the bulk solution in the manufacturing vessel isbrought up to a final volume of about 100 L (e.g., about 100 Kg), usingreserved WFJ. The resulting bulk solution is stirred for at least about10 minutes such as about 15 minutes, at least about 30 minutes, or,e.g., at least about 40 minutes or for a sufficient time to ensureuniformity of the bulk solution. The final bulk solution is checked toconfirm that the pH of the solution is about 7.2, e.g., about 6.9-about7.5, such as, e.g., about 7.1-about 7.3, e.g., about 7.2. The pH of thesolution is adjusted, if necessary, with stirring and final pHconfirmation repeated, as necessary.

Part 2. Filtration 2.1 Offline Filtration

After completion of the preparation of the bulk solution (e.g.,compounding activity), the filtration process is initiated under laminarair flow (LAF).

Prior to initiation of the filtration process, a 0.2 μm capsule orcartridge filter is integrity tested using a water bubble point testagainst the filter manufacturer's specification. The result should be apressure of not less than 46 psi under a filtration pressure limit ofabout 0.8 Kg/cm² to about 1.8 Kg/cm².

Prior to the start of filtration activity, the filtration unit isflushed with about 200 mL to about 220 mL of the bulk solution. The bulksolution is held inside of the filtration unit for about 1 minute, about1.5 minutes, about 2 minutes, about 2.5 minutes, or, e.g., about 3minutes during the flush. The bulk solution used for the flush is thendiscarded. The flushing procedure is repeated two additional times for atotal of 3 flushes.

After flushing, filtration of the bulk solution is initiated. The bulksolution is filtered through the pre-sterilized, tested, and flushed 0.2μm capsule or cartridge filter, e.g., a polyethersulfone (PES) capsulefilter. All filtrate is collected in a sterile receiving vessel(filtrate receiving vessel).

Upon completion of filtration, the filtrate within the sterile receivingvessel is overlayed with 0.2 μm-filtered nitrogen.

The receiving vessel is transferred to a sterile storage area and storedunder laminar air flow until initiation of the filling activity.

A post-filtration integrity test of the filter is performed using awater bubble point test. The result should be a pressure of not lessthan 39.2 psi under a filtration pressure limit of about 0.8 Kg/cm² toabout 1.8 Kg/cm².

2.2 Online Filtration

Prior to the initiation of filling and capping activity, the bulksolution is filtered through another 0.24 pre-sterilized capsule orcartridge filter, e.g., a polyethersulfone (PES) capsule filter.

Pre-integrity filter testing is performed using a water bubble pointtest against the filter manufacturer's specification. The result shouldbe a pressure of not less than 46 psi under a filtration pressure limitof about 0.8 Kg/cm² to about 1.8 Kg/cm². The filter is then connected tothe filling line through a pre-sterilized vessel, e.g., buffer tank.

Prior to the initiation of filtration activity, the filter/filtrationunit is flushed with about 200 to about 220 mL of the bulk solution. Thebulk solution is held within the filtration unit for about 1 minute,such as about 2 minutes, about 2.5 minutes, or, e.g., about 3 minutesduring this flushing process and is then discarded. The flushing processis repeated at least two additional times for a total of at least about3 flushes, with the bulk solution used for flushing discarded after eachflush.

After completely discarding the filter flush solution, the entirequantity of remaining bulk solution is filtered into the sterile vessel,e.g., the sterile buffer tank.

The filling activity is then initiated.

Upon the completion of the filling activity, a post-filtration integritytest of the filter is performed using a water bubble point test. Theresult should be a pressure of not less than 39.2 psi under a filtrationpressure limit of about 0.8 Kg/cm² to about 1.8 Kg/cm².

Part 3. Filling and Capping

Suitable sterile containers, such as sterile vials, are each filled to avolume of about 2.6 mL to about 2.8 mL (˜2.62 g-˜2.82 g), such as about2.7 mL (about 2.72 g).

After filling, the head space of each vial is flushed with filterednitrogen, e.g., using a minimum nitrogen flow of about 2 L/min.

The first about 30 vials are collected and identified as the initialsystem flush.

Checks for proper processing, e.g., proper filling volume and vialsealing, are performed intermittently (e.g., at least 2 times, at least5 times, at least 10 times, at least 20 times, at least 50 times ormore) during any single batch filling procedure. The filling process isstopped, adjusted, or otherwise corrected if filling processes do notmeet previously defined standards (e.g., of fill volume, air-tightsealing of vials, etc.). Packaged product identified as not meetingpredefined acceptance criteria are rejected.

Example 4

The following manufacturing process can be used to manufacture acomposition according to Formulation B or Formulation C of Table 5,e.g., Composition B or Composition C of Table 6 (Example 2).

Part 1. Bulk Solution Manufacturing (100 L) 1.1 Preparation of PolymerPhase Solution

A first (filter no. 1) and a second (filter no. 2) 0.2 μm capsule filterare each integrity-tested using a water bubble point test against thefilter manufacturer's specification(s). The result of each test shouldbe a pressure of not less than 46.0 psi under a filtration pressurelimit of about 0.8 Kg/cm² to about 1.8 Kg/cm². Upon completion ofintegrity testing, filters are flushed with nitrogen to remove anyresidual water from the filter pores.

The outlet of filter no. 2 is connected to the inlet of filter No. 1using a suitable connection mechanism, such as Pharma 50 silicone tubingof a suitable length, such as about 60 cm. The outlet of filter no. 1 isconnected to a diaphragm valve. The inlet of filter no. 2 is connectedto a suitable connection mechanism, such as Pharma 50 silicone tubing ofsuitable length, such as about 2.30 meters. The entire assembly issterilized using a suitable sterilization method such as autoclaving.During sterilization, e.g., while autoclaving, the diaphragm valve ismaintained in an open position. Upon completion of sterilization, e.g.,after autoclaving, the diaphragm valve is closed under asepticconditions. The entire assembly is then connected to an emptymanufacturing vessel (e.g., a “reactor vessel”).

The manufacturing vessel/reactor vessel is sterilized with about 120 Kgof water for injection (WFI). This establishes a sterilized “reactorvessel” or “SIP vessel”.

About 120 Kg of water for injection (WFI) at a temperature of not lessthan about 70° C. is collected in a manufacturing vessel, such as, e.g.,a stainless-steel (SS) vessel.

The WFI is cooled to about 20° C.-about 25° C., such as by circulatingthe water through a water jacket. While cooling, e.g., simultaneouslywith cooling, 0.2μ-filtered nitrogen is bubbled through the WFI, withall WFI collected in the manufacturing vessel.

The dissolved oxygen content of the WFI is routinely tested to ensurethat the WFI reaches a dissolved oxygen content of no more than 2 ppm.

Nitrogen bubbling is continued throughout bulk solution manufacturing.

After completion of empty reactor sterilization, about 50 Kg of the 120Kg of WFI is transferred to a second manufacturing vessel, e.g., astainless-steel manufacturing vessel, to be used in the preparation of adrug phase and bringing composition(s) up to volume.

While maintaining the temperature of the remaining about 70 Kg WFI inthe reactor vessel between about 73° C. and 78° C., a suitable stirrerin the reactor vessel is set to a stirrer speed of about 125 rpm±about50 rpm. The mixing speed is adjusted as necessary based on/according tothe equipment and batch, e.g., vessel geometry and the stirring dynamicsduring the manufacture of the batch.

The required quantity of gellan gum NF (national formulary) is added tothe reactor vessel and stirring is maintained at about 125 rpm±about 50rpm for at least about 30 minutes, such as about 60 mins, or for asufficient time to ensure complete dissolution of the gellan gum. Thesolution is maintained at a temperature of between about 73° C. andabout 78° C. during the continuous stirring.

Optionally, the total required quantity of a preservative component,e.g., benzalkonium chloride is added. In aspects, the resultingcomposition is mixed for a sufficient period of time to ensure that thepreservative component constituent(s) are completely dissolved.

After complete dissolution, the solution is cooled to between about 20°C. and about 25° C. under constant stirring. This establishes the“polymer phase”.

The polymer phase is sterilized at set temperature of about 122.0° C.for about 20 minutes while constantly stirring at speed of about 125rpm±about 50 rpm.

Upon completion of sterilization, the polymer phase is cooled to about25° C. While cooling, when the temperature of the polymer phase reachesabout 60° C., the stirring speed is increased to a stirring speed ofabout 250 rpm±50 rpm.

1.2 Preparation of Drug Phase Solution

About 50 Kg of the reserved, cooled WFI is collected in a suitablemanufacturing vessel. A suitable stirrer in the manufacturing vessel isset to a stirring speed of about 300 rpm±50 rpm. The mixing speed isadjusted as necessary based on/according to the equipment and batch,e.g., vessel geometry and the stirring dynamics during the manufactureof the batch.

The total required quantity of solubilizer, penetration enhancer, orcompound(s) providing both solubilization and penetration enhancementeffect, e.g., polysorbate 80, tocopherol polyethylene glycol succinate(TPGS), polyoxyl castor oil (e.g., polyethoxylated castor oil, such aspolyoxyl 35 castor oil), or, e.g., protein/peptide enhancers (e.g.,poly-arginine or polyserine) is optionally added to the manufacturingvessel. In certain formulations, such one or more ingredients is absentfrom the composition (e.g., is/are not added). The container(s) used toadd each such ingredient is/are rinsed multiple times, e.g., about 5times, with approximately 50 mL of WFI each time. The rinses are addedto the manufacturing vessel under stirring. Stirring is continuous fromthe beginning of the process to the end of the process, unless otherwiseindicated.

The total required quantity of bimatoprost compound is added to themanufacturing vessel. The container used to add the bimatoprost compoundis rinsed multiple times, e.g., about 3 times, with approximately 25 mLof WFI each time. The rinses are added to the manufacturing vessel.Stirring is continued for at least about 15 minutes, such as at leastabout 30 minutes, at least about 45 minutes, at least about 60 minutes,or at least about 65 minutes, or for a sufficient time to ensurecomplete dissolution of the bimatoprost compound and compositionuniformity.

The total required quantity of timolol compound is added to themanufacturing vessel. The container used to add the timolol compound isrinsed multiple times, e.g., about 3 times, with approximately 25 mL ofWFI each time. The rinses are added to the manufacturing vessel.Stirring is continued for at least about 15 minutes, such as at leastabout 30 minutes, at least about 45 minutes, at least about 60 minutes,or at least about 65 minutes, or for a sufficient time to ensurecomplete dissolution of the timolol compound and composition uniformity.

The total required quantity of mannitol is added to the solution in themanufacturing vessel. The resulting composition is mixed for a suitableperiod of time to allow the mannitol to completely dissolve.

Upon the complete dissolution of the mannitol, the total requiredquantity of tromethamine is added to the solution. The resultingcomposition is mixed for a sufficient period of time, such as about 10minutes, to ensure complete dissolution of the tromethamine.

The composition is checked for clarity. Stirring is continued untilvisual clarity is achieved.

The volume is brought to about 55 L using previously reserved WFI. Thecomposition is stirred for at least about 10 minutes, e.g., at leastabout 15 minutes, at least about 20 minutes, or for a sufficient periodof time to ensure composition uniformity. This establishes the “drugphase”.

An industry standard sampling protocol is used to sample and test thedrug phase to ensure that the phase meets pre-establishedspecification(s). Upon acceptance, the drug phase is transferred to thesterilized polymer phase via aseptic filtration (see below).

1.3 Aseptic Filtration of Drug Phase into Sterile Polymer Phase

Aseptic filtration of the drug phase into the sterile polymer phase isperformed at a filtration pressure of about 0.8 Kg/cm²-about 1.8 Kg/cm².

Prior to beginning the aseptic filtration, the weight of the drug phaseis noted. About 55 Kg of the drug phase (which can be referred to as the“concentrated drug phase”) is filtered into the reactor vesselcontaining the polymer phase through the two sterilized 0.2 μm filtersconnected in series.

WFI is then passed through the filters a number of times, such as abouttwo times with about 2.5 L of WFI each time, and the filtrate added tothe reactor vessel each time to ensure all required drug phase is addedinto the reactor vessel. The resulting composition is then stirred forabout 1 hour at a speed of about 250 rpm±about 50 rpm, or for asufficient period of time (and at a suitable speed) to ensurecomposition uniformity.

A post-filtration integrity test of the filter is performed using awater bubble point test. The result should be a pressure of not lessthan 34.8 psi under a filtration pressure limit of about 0.8 Kg/cm² toabout 1.8 Kg/cm².

The pH of the composition is adjusted using one or more pH adjustingagents. The pH of the solution is adjusted by the addition or one ormore pH adjusting agents, with the solution sufficiently mixed aftereach addition such that the composition has a uniform pH prior to (1)sampling for pH, and (2) applying further pH adjustment as needed.Composition pH is adjusted to a pH of about 6.2 to about 7, such as,e.g., ˜6.3, ˜6,4, ˜6.5, ˜6.6, ˜6.7, ˜6.8, or ˜6.9, using the pHadjusting agent(s).

Part 2. Filtration

Filtration of the final combined composition (bulk solution) is thenperformed using a suitable filter such as an 8 μm PP2 MidiCap® filter(Sartorius).

Before initiating filtration activity, a sterilized 8.0 μm polypropylenefilter is flushed with about 100 mL to about 120 mL of bulk solution anumber of times such as about 3 times. During each flush, thecomposition is held in the filtration unit for an extended period oftime, such as about 2 minutes, prior to discarding each flush. Uponcompletion of flushing, filtration of the bulk solution is performedwith the filtrate collected in a sterile receiving vessel.

Part 3. Filling and Capping

Suitable sterile containers, such as sterile vials, are each filled to avolume of about 2.6 mL to about 2.8 mL (about 2.62 g to about 2.82 g),such as ˜2.7 mL (about 2.72 g).

After filling, the head space of each vial is flushed with filterednitrogen, e.g., using a minimum nitrogen flow of about 2 L/min.

What is claimed is:
 1. A method of treating elevated intraocularpressure, glaucoma, or both, in a mammalian eye, the method comprisingadministration of an effective amount of a composition comprising (1)about 0.005% w/v-about 0.02% w/v of a bimatoprost compound; (2) about0.4% w/v-about 0.8% w/v of a timolol compound; (3) about 0.003%-about0.007% of a quaternary ammonium salt; and (4) about 0.25% w/v-about 2.5%w/v of a penetration enhancer component, wherein the composition isfurther characterized by (a) the ratio of the quaternary ammonium saltto the penetration enhancer component is between about 1:35-about 1:840;(b) the ratio of the bimatoprost compound to the penetration enhancercomponent is about 1:12.5-about 1:500; (c) the ratio of the timololcompound to the penetration enhancer component is between about3.2:1-1:6.3; or (d) any combination of (a)-(c) are true.
 2. The methodof claim 1, wherein the effective amount is one or two drops ofcomposition administered to the affected mammalian eye once or twice perday.
 3. The method of claim 2, wherein the effective amount is one dropof composition administered to the affected mammalian eye once per day.4. The method of claim 2, wherein the method is clinically demonstratedto be as effective or detectably or significantly more effective thantreatment of the same or at least essentially the same condition withabout the same amount of a reference composition consisting of 0.3 mg/mL(0.03% w/v) bimatoprost; 6.8 mg/mL (0.68% w/v) timolol maleate (anamount equivalent to 5 mg/mL or 0.5% w/v timolol); 0.05 mg (0.005% w/v)benzalkonium chloride; sodium chloride; sodium phosphate dibasicheptahydrate; citric acid monohydrate; optionally hydrochloric acid,sodium hydroxide, or both; and water, for about the same administrationperiod as determined by one or more well-controlled and adequateclinical studies performed in compliance with generally prevailingregulatory authority standards.
 5. The method of claim 2, wherein themethod comprises administration of 1-2 drops of composition once ortwice daily over an effective treatment period, and the application ofthe method is clinically demonstrated to result in a significantlyreduced frequency of hyperemia compared to treatment of the same or atleast essentially the same condition with about the same amount of areference composition consisting of 0.3 mg/mL (0.03% w/v) bimatoprost;6.8 mg/mL (0.68% w/v) timolol maleate (an amount equivalent to 5 mg/mLor 0.5% w/v timolol); 0.05 mg (0.005% w/v) benzalkonium chloride; sodiumchloride; sodium phosphate dibasic heptahydrate; citric acidmonohydrate; optionally hydrochloric acid, sodium hydroxide, or both;and water.
 6. The method of claim 1, wherein the ratio of the quaternaryammonium salt to the penetration enhancer component in the compositionis between about 1:35-about 1:840.
 7. The method of claim 7, wherein theratio of the quaternary ammonium salt to the penetration enhancercomponent in the composition is about 1: about 100-about 1: about 300.8. The method of claim 8, wherein the ratio of the quaternary ammoniumsalt to the penetration enhancer component in the composition is about1: about
 200. 9. The method of claim 1, wherein the bimatoprost compoundin the composition is bimatoprost base, and the bimatoprost base makesup about 0.01% w/v of the composition.
 10. The method of claim 1,wherein the ratio of the bimatoprost base to the penetration enhancercomponent in the composition is about 1: about 1.3-about 1: about 500.11. The method of claim 9, wherein the ratio of the bimatoprost base tothe penetration enhancer component in the composition is about 1: about20-about 1: about
 200. 12. The method of claim 10, wherein the ratio ofthe bimatoprost base to the penetration enhancer component in thecomposition is about 1: about
 100. 13. The method of claim 1, whereinthe timolol compound in the composition is a salt of timolol.
 14. Themethod of claim 13, wherein the salt of timolol in the composition istimolol maleate, and the timolol maleate makes up about 0.68% w/v of thecomposition.
 15. The method of claim 1, wherein the ratio of the timololcompound to the penetration enhancer component in the composition isbetween about 3.2: about 1-about 1 about 6.3.
 16. The method of claim15, wherein the ratio of the timolol compound to the penetrationenhancer component in the composition is between about 2: about 1-about1 about
 3. 17. The method of claim 13, wherein the ratio of the timololcompound to the penetration enhancer component in the composition isabout 1: about 1.5.
 18. The method of claim 1, wherein the bimatoprostcompound in the composition is bimatoprost base present in thecomposition in an amount representing about 0.01% w/v of the compositionand the timolol compound in the composition is timolol maleate presentin the composition in an amount representing about 0.68% w/v of thecomposition.
 19. The method of claim 4, wherein the bimatoprost compoundin the composition is bimatoprost base present in the composition in anamount representing about 0.01% w/v of the composition and the timololcompound in the composition is timolol maleate present in thecomposition in an amount representing about 0.68% w/v of thecomposition.
 20. The method of claim 5, wherein the bimatoprost compoundin the composition is bimatoprost base present in the composition in anamount representing about 0.01% w/v of the composition and the timololcompound in the composition is timolol maleate present in thecomposition in an amount representing about 0.68% w/v of thecomposition.